Acyloxyalkyl Carbamate Prodrugs of Alpha-Amino Acids, Methods of Synthesis and Use

ABSTRACT

Acyloxyalkyl carbamate prodrugs of α-amino acids, pharmaceutical compositions thereof, methods of making acyloxyalkyl carbamate prodrugs of α-amino acids and methods of using acyloxyalkyl carbamate prodrugs of α-amino acids, and pharmaceutical compositions thereof to treat a disease are disclosed. Acyloxyalkyl carbamate prodrugs of α-amino acids suitable for oral administration using sustained release dosage forms are also disclosed.

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application Ser. No. 60/833,774 filed Jul. 28, 2006, whichis incorporated by reference herein in its entirety.

FIELD

The disclosure relates to acyloxyalkyl carbamate prodrugs of α-aminoacids, methods of making acyloxyalkyl carbamate prodrugs of α-aminoacids, methods of using acyloxyalkyl carbamate prodrugs of α-aminoacids, and pharmaceutical compositions comprising acyloxyalkyl carbamateprodrugs of α-amino acids to treat disease. The disclosure also relatesto acyloxyalkyl carbamate prodrugs of α-amino acids suitable for oraladministration using sustained release dosage forms.

BACKGROUND

Schizophrenia is a psychotic disorder associated with positive,negative, and cognitive symptoms, neuropsychological deficits, and poorsocial functioning. Classical theories of schizophrenia have focused onabnormal dopaminergic neurotransmission, and clinical treatments forschizophrenia include use of the typical (“first generation”) andatypical (“second generation”) antipsychotics, which function in part asdopamine antagonists. Examples of typical antipsychotics (orneuroleptics) include chlorpromazine, haloperidol, fluphenazine, andthioridazine. Examples of atypical antipsychotic include clozapine,risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, andsertindole.

Recent theories have postulated that schizophrenia is associated withdysfunction or dysregulation of neurotransmission mediated at brainN-methyl-D-aspartate (NMDA)-type glutamate receptors (Javitt, D. C. andZukin, S. R., Am. J. Psychiatry 1991, 148, 1301-1308; Javitt, U.S. Pat.No. 5,837,730; Javitt et al., U.S. Pat. No. 5,854,286; Javitt, U.S. Pat.No. 6,162,827; Javitt, U.S. Pat. No. 6,355,681; Javitt, U.S. Pat. No.6,361,957; Tsai and Coyel, U.S. Pat. No. 6,667,297; Tsai and Coyel, U.S.Pat. No. 6,974,821; Javitt, U.S. Application Publication No.2002/0010212; Javitt, U.S. Application Publication No. 2002/0013364;Tsai and Coyel, U.S. Application Publication No. 2002/0035145; U.S.Application Publication No. 2002/0161048; Javitt, U.S. ApplicationPublication No. 2002/0183390; Tsai and Coyel, U.S. ApplicationPublication No. 2002/0193429; Tsai and Coyel, U.S. ApplicationPublication No. 2004/0092530; Javitt, U.S. Application Publication No.2005/0159488; and Tsai and Coyet, U.S. Application Publication No.2005/0250851). NMDA glycine-site agonists (including glycine, D-serine,and D-alanine) and partial agonists (e.g., D-cycloserine) inducesignificant improvement in negative and cognitive symptoms inschizophrenics (Javitt et al., Am. J. Psychiatry 1994, 151, 1234-1236;Heresco-Levy et al., Br. J. Psychiatry 1996, 169, 610-617; Heresco-Levyet al., Arch. Gen. Psychiatry 1999, 56, 29-36; Heresco-Levy et al., Am.J. Psychiatry 2002, 159, 480-482; Goff, et al., Am. J. Psychiatry 1995,152, 1213-1215; Goff et al., Arch. Gen. Psychiatry 1999, 56, 21-27; vanBerckel et al., Biol. Psychiatry 1996, 40, 1298-1300; Tsai et al., Biol.Psychiatry 1998, 44, 1081-1089; and Tsai et al., Biol. Psychiatry 2006,59, 230-234, each of which is incorporated by reference herein in itsentirety), supporting the role of glutamatergic hypofunctioning in thispsychotic disorder. While clinical studies of schizophrenia using NMDAagonists as single agents have been undertaken (e.g., van Berckel etal., Biol. Psychiatry 1996, 40, 1298-1300), in the majority of thepublished studies these compounds were administered adjunctively witheither conventional neuroleptics or atypical antipsychotic drugs toaugment the activity of standard therapies.

Synaptic levels of the endogenous agonists for the NMDA receptor glycinesite, for example, glycine and D-serine, are regulated in the mammalianbrain by the activity of reuptake transporters. Inhibition of suchtransporters can potentiate signaling by the endogenous agonist and canprovide an alternative to direct administration of the agonist itself.High affinity glycine transporters are encoded by two separate genes:GLYT1 and GLYT2 (Supplisson et al., FEBS Lett. 2002, 529, 93-101). GLYT1is expressed abundantly in glial cells and is believed to be a primaryregulator of glycine concentrations at the NMDA receptor. Sarcosine(N-methylglycine) is a transported, competitive inhibitor of GLYT1 thathas been dosed adjunctively with typical and atypical antipsychoticagents and is shown to improve positive, negative, and cognitive symptomdomains in schizophrenic patients (Tsai et al., Biol. Psychiatry 2004,55, 452-456; and Lane et al., Arch. Gen. Psychiatry 2005, 62,1196-1204).

1-Aminocyclopropanecarboxylic acid is frequently characterized in theliterature as an NMDA partial agonist acting at the glycine site,although a recent detailed mechanistic analysis supports concurrent highaffinity, fully efficacious agonist activity at the glycine site andlower affinity antagonist activity at the glutamate binding site of theNMDA heterodimer (Nahum-Levy et al., Mol. Pharmacol. 1999, 56,1207-1218). The utility of 1-aminocyclopropanecarboxylic acid as therapyfor a variety of neurodegenerative and neuropsychiatric disorders ispredicated on its functional antagonism of NMDA neurotransmission atrelatively high doses (Trullas and Skolnick., U.S. Pat. No. 5,086,072;Skolnick et al., U.S. Pat. No. 5,428,069; Maccecchini, U.S. Pat. No.5,523,323; Skolnick et al., U.S. Pat. No. 6,017,957; Schneider, U.S.Application Publication No. 2004/0087596; Davis and Ressler, U.S.Application Publication No. 2004/0208923; and Davis and Ressler, U.S.Application Publication No. 2005/0096396).

The sub-optimal biopharmaceutical properties of α-amino acid NMDAglycine-site agonists such as glycine, D-serine, D-alanine, and1-aminocyclopropanecarboxylic acid, and GLYT1 inhibitors such assarcosine can significantly limit the clinical utility of these agentsin the treatment of schizophrenia and other CNS disorders. Glycine haslimited blood-brain-barrier permeability and enormous doses (about 30-60g/day) must be administered to produce a beneficial effect inschizophrenics. While oral therapy with D-serine and sarcosine hasallowed for more pharmaceutically practical doses (about 2 g/day), theintrinsically rapid clearance of these amino acids has necessitatedfrequent daily administration (t.i.d), providing a therapeutic regimenthat discourages compliance and is inconvenient for patients. Moreover,the short half-lives of these amino acids ensure that plasma levelsfluctuate widely, potentially limiting exposure to optimum therapeuticlevels throughout the day.

This disclosure satisfies an unmet need for new medicinal agents thatcan provide for stimulation of NMDA receptor signaling pathways and aresuitable for administration to patients in need of such therapy oncedaily or multiple times daily. Such compounds, and pharmaceuticalcompositions comprising the compounds, can be useful for the treatmentof, for example, positive, negative, and/or cognitive symptom domains inschizophrenics, and may be administered alone or adjunctive to otherantipsychotic medicaments. These compounds, and pharmaceuticalcompositions comprising the compounds, can also be useful for treatmentof other neuropsychiatric and neurodegenerative diseases such asdementia, depression, attention-deficit disorders, learning and memorydisorders, and other diseases where NMDA-mediated neurotransmission isimplicated.

SUMMARY

In a first aspect, compounds of Formula (I):

pharmaceutically acceptable salts thereof, and pharmaceuticallyacceptable solvates of any of the foregoing, are provided, wherein:

R¹ is chosen from acyl, substituted acyl, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R² and R³ are independently chosen from hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl, or R² and R³, together with the carbon atomto which they are bonded, form a ring chosen from a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, and substitutedcycloheteroalkyl ring;

R⁴ is chosen from hydrogen and methyl;

R⁵ is chosen from hydrogen, methyl, and hydroxymethyl; and

R⁶ is hydrogen, or R⁵ and R⁶ together with the carbon atom to which theyare bonded form a ring chosen from a 1,1-cyclopropane ring andsubstituted 1,1-cyclopropane ring.

In a second aspect, pharmaceutical compositions comprising at least onepharmaceutically acceptable vehicle and a therapeutically effectiveamount of at least one compound of Formula (I) are provided.

In a third aspect, sustained release oral dosage forms comprising atleast one compound of Formula (I) are provided.

In a fourth aspect, methods of synthesizing compounds of Formula (I),pharmaceutically acceptable salts thereof, and pharmaceuticallyacceptable solvates of any of the foregoing are provided, comprisingcontacting a compound of Formula (II) with a compound of Formula (III)to provide the compounds of Formula (I):

wherein:

R¹, R², R³, R⁴, R⁵ and R⁶ are as defined above; and

R⁷ and R⁸ are independently chosen from hydrogen, acylamino, acyloxy,alkoxycarbonylamino, alkoxycarbonyloxy, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl,substituted arylalkyl, carbamoyloxy, dialkylamino, heteroaryl,substituted heteroaryl, hydroxy, and sulfonamido, or R⁷ and R⁸ togetherwith the atoms to which they are bonded form a ring chosen from asubstituted cycloalkyl, substituted cycloheteroalkyl, and substitutedaryl ring.

In a fifth aspect, methods of treating a disease in a patient areprovided, the methods comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of a colonicallyabsorbable form of at least one α-amino acid.

In a sixth aspect, methods of treating a disease in a patient areprovided, the methods comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of at least onecompound of Formula (I).

These and other aspects are provided by the disclosure herein ofacyloxyalkyl carbamate prodrugs of α-amino acids, pharmaceuticalcompositions of acyloxyalkyl carbamate prodrugs of α-amino acids,methods of making acyloxyalkyl carbamate prodrugs of α-amino acids, andmethods of using acyloxyalkyl carbamate prodrugs of α-amino acids and/orpharmaceutical compositions thereof to treat various diseases such ascognitive disorders, anxiety disorders, schizophrenia, psychosis,substance-related or addictive disorders, pain, obesity, eatingdisorders, dyskinesias, neuropsychiatric disorders, neurodegenerativedisorders, urinary incontinence, neuronal damage, emesis, and sleepdisorders. In certain embodiments, an acyloxyalkyl carbamate prodrug ofan α-amino acid is an acyloxylalkyl carbamate prodrug of an α-amino acidchosen from D-serine, D-alanine, 1-aminocyclopropanecarboxylic acid, andsarcosine.

DETAILED DESCRIPTION Definitions

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,—CONH₂ is a moiety bonded through the carbon atom.

“Acyl,” by itself or as part of another substituent, refers to theradical —C(O)R³⁰, where R³⁰ is chosen from hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, andheteroarylalkyl as defined herein. Examples of acyl groups include, butare not limited to, formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

“Acylamino,” by itself or as part of another substituent, refers to theradical —NR³¹OC(O)R³², where R³¹ and R³² are independently chosen fromhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,heteroalkyl, heteroaryl, and heteroarylalkyl as defined herein. Examplesof acylamino groups include, but are not limited to formamido,acetamido, and benzamido.

“1-Acyloxy-alkyl carbamate” refers to an N—1-acyloxy-alkoxycarbonylderivative of an α-amino acid as encompassed by compounds of Formula (I)disclosed herein.

“Alkyl,” by itself or as part of another substituent, refers to asaturated or unsaturated, branched or straight-chain monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. Examples ofalkyl groups include, but are not limited to, methyl; ethyls such asethanyl, ethenyl, and ethynyl; propyls such as propan-1-yl, propan-2-yl,prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, but-1-en-1-yl,but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl,but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double, and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the terms “alkanyl,”“alkenyl,” and “alkynyl” are used. In certain embodiments, alkyl groupscomprise from 1 to 20 carbon atoms, in certain embodiments, from 1 to 6carbon atoms, and in certain embodiments, from 1 to 3 carbon atoms.

“Alkanyl,” by itself or as part of another substituent, refers to asaturated, branched or straight-chain alkyl radical derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane. Examples of alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl),2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (1-butyl), etc.;and the like.

“Alkenyl,” by itself or as part of another substituent, refers to anunsaturated, branched or straight-chain alkyl radical having at leastone carbon-carbon double bond derived by the removal of one hydrogenatom from a single carbon atom of a parent alkene. The group may be ineither the cis or trans conformation about each double bond. Examples ofalkenyl groups include, but are not limited to, ethenyl; propenyls suchas prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl),prop-2-en-2-yl, butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, etc.; and the like.

“Alkynyl,” by itself or as part of another substituent, refers to anunsaturated, branched or straight-chain alkyl radical having at leastone carbon-carbon triple bond derived by the removal of one hydrogenatom from a single carbon atom of a parent alkyne. Examples of alkynylgroups include, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyloxy,” by itself or as part of another substituent, refers to theradical —OC(O)R³³, where R³³ is chosen from alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, andheteroarylalkyl, as defined herein. Examples of acyloxy groups include,but are not limited to acetoxy, isobutyroyloxy, benzoyloxy,phenylacetoxy, and the like.

“Alkoxy,” by itself or as part of another substituent, refers to theradical —OR⁵⁰ where R⁵⁰ represents an alkyl or cycloalkyl group, asdefined herein. Examples of alkoxy groups include, but are not limitedto, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like.

“Alkoxycarbonyl,” by itself or as part of another substituent refers tothe radical —C(O)OR⁵¹ where R⁵¹ represents an alkyl group, as definedherein. Examples of alkoxycarbonyl groups include, but are not limitedto, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,and the like.

“Alkoxycarbonylamino,” by itself or as part of another substituent,refers to the radical —NR³⁶C(O)—OR³⁷ where R³⁶ is chosen from alkyl andcycloalkyl; and R³⁷ is chosen from alkyl, cycloalkyl, cycloheteroalkyl,aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl, asdefined herein. Examples of alkoxycarbonylamino groups include, but arenot limited to, methoxycarbonylamino, tert-butoxycarbonylamino, andbenzyloxycarbonylamino.

“Alkoxycarbonyloxy,” by itself or as part of another substituent, refersto the radical —OC(O)—OR³⁸ where R³⁸ is chosen from alkyl andcycloalkyl, as defined herein. Examples of alkoxycarbonyloxy include,but are not limited to, methoxycarbonyloxy, ethoxycarbonyloxy, andcyclohexyloxycarbonyloxy.

“Alkylamino,” by itself or as part of another substituent, refers to theradical —NHR⁵³ where R⁵³ is chosen from alkyl and cycloalkyl, as definedherein.

“α-Amino acid” refers to a compound of Formula (III):

wherein R⁴ is chosen from hydrogen and methyl, R⁵ is chosen fromhydrogen, methyl, and hydroxymethyl; and R⁶ is hydrogen; or R⁵ and R⁶together with the carbon atom to which they are bonded form a ringchosen from a 1,1-cyclopropane ring and a substituted 1,1-cyclopropanering. In certain embodiments, an α-amino acid is chosen from D-serine,D-alanine, 1-aminocyclopropanecarboxylic acid, and sarcosine

“Aryl,” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem. Aryl encompasses 5- and 6-membered carbocyclic aromatic rings,for example, benzene; bicyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, naphthalene, indane, andtetralin; and tricyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, fluorene. Aryl encompassesmultiple ring systems having at least one carbocyclic aromatic ringfused to at least one carbocylic aromatic ring, cycloalkyl ring, orheterocycloalkyl ring. For example, aryl includes 5- and 6-memberedcarbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkylring containing one or more heteroatoms chosen from N, O, and S. Forsuch fused, bicyclic ring systems wherein only one of the rings is acarbocyclic aromatic ring, the point of attachment may be at thecarbocyclic aromatic ring or the heterocycloalkyl ring. Examples of arylgroups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexylene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene, and the like. In certain embodiments, aryl groups havefrom 5 to 20 carbon atoms, and in certain embodiments, from 5 to 12carbon atoms. In certain embodiments, aryl has from 6 to 10 carbonatoms.

“Arylalkyl,” by itself or as part of another substituent, refers to anacyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Examples of arylalkyl groups include, but are not limitedto, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl, and the like. Where specific alkyl moietiesare intended, the nomenclature “arylalkanyl,” “arylalkenyl,” or“arylalkynyl” is used. In certain embodiments, an arylalkyl group isC₇₋₃₀ arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is C₁₋₁₀ and the aryl moiety is C₆₋₂₀ and in certainembodiments, an arylalkyl group is C₇₋₂₀ arylalkyl, e.g., the alkanyl,alkenyl or alkynyl moiety of the arylalkyl group is C₁₋₈ and the arylmoiety is C₆₋₁₂. In certain embodiments, arylalkyl is C₆₋₁₀ arylalkyl.

“AUC” is the area under a curve representing the concentration of acompound or metabolite thereof in a biological fluid in a patient as afunction of time following administration of the compound to thepatient. In certain embodiments, the compound is a prodrug and themetabolite is a drug. Examples of biological fluids include plasma,blood, and cerebrospinal fluid. The AUC may be determined by measuringthe concentration of a compound or metabolite thereof in a biologicalfluid such as the plasma or blood using methods such as liquidchromatography-tandem mass spectrometry (LC/MS/MS), at various timeintervals, and calculating the area under the plasmaconcentration-versus-time curve. Suitable methods for calculating theAUC from a drug concentration-versus-time curve are well known in theart. For example, an AUC for an α-amino acid may be determined bymeasuring the concentration of the α-amino acid in the plasma or bloodof a patient following administration of a compound of Formula (I) tothe patient.

“C_(max)” is the maximum concentration of a drug in the plasma or bloodof a patient following administration of a dose of the drug or prodrugto the patient.

“T_(max)” is the time to the maximum concentration (C_(max)) of a drugin the plasma or blood of a patient following administration of a doseof the drug or prodrug to the patient “Carbamoyl,” by itself or as partof another substituent, refers to the radical —C(O)NR³⁹R⁴⁰ where R³⁹ andR⁴⁰ are independently chosen from hydrogen, alkyl, cycloalkyl, and aryl,as defined herein.

“Carbamoyloxy,” by itself or as part of another substituent refers tothe radical —OC(O)₂NR⁴¹R⁴² where R⁴¹ and R⁴² are independently chosenfrom hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,heteroalkyl, heteroaryl, and heteroarylalkyl, as defined herein, or R⁴¹and R⁴² together with the nitrogen atom to which they are bonded form aring chosen from a cycloheteroalkyl and a heteroaryl ring.

“Cleave” refers to breakage of chemical bonds and is not limited tochemical or enzymatic reactions or mechanisms unless clearly intended bythe context.

“Compounds” of Formula (I) disclosed herein include any specificcompounds within the formula having a structure is disclosed herein.Compounds may be identified by their chemical structure and/or chemicalname. If the chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound.

The compounds described herein may comprise one or more chiral centersand/or double bonds and therefore may exist as stereoisomers such asdouble-bond isomers (i.e., geometric isomers), enantiomers, anddiastereomers. Accordingly, any chemical structures within the scope ofthe specification depicted, in whole or in part, with a relativeconfiguration encompass all possible enantiomers and stereoisomers ofthe illustrated compounds including the stereoisomerically pure form(e.g., geometrically pure, enantiomerically pure, or diastereomericallypure) and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures may be resolved into their component enantiomersor stereoisomers using separation techniques and stereoisomerically pureforms may be synthesized using chiral synthesis techniques well known tothe skilled artisan.

Compounds of Formula (I) include, but are not limited to, opticalisomers of compounds of Formula (I), racemates thereof, and othermixtures thereof. In such embodiments, the single enantiomers ordiastereomers, i.e., optically active forms, may be obtained byasymmetric synthesis or by resolution of the racemates. Resolution ofthe racemates may be accomplished, for example, by conventional methodssuch as crystallization in the presence of a resolving agent, orchromatography, using, for example, a chiral high-pressure liquidchromatography (HPLC) column. In addition, compounds of Formula (I)include Z- and E-forms (or cis- and trans-forms) of compounds withdouble bonds. In embodiments in which compounds of Formula (I) exist invarious tautomeric forms, compounds of Formula (I) include any and alltautomeric forms of the compound.

The compounds of Formula (I) may also exist in several tautomeric formsincluding the enol form, the keto form, and mixtures thereof.Accordingly, the chemical structures depicted herein encompass any andall possible tautomeric forms of the illustrated compounds. Thecompounds of Formula (I) also include isotopically labeled compoundswhere one or more atoms have an atomic mass different from the atomicmass conventionally found in nature. Examples of isotopes that may beincorporated into the compounds disclosed herein include, but are notlimited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms and as N-oxides. In general, compounds may be hydrates, solvates,or N-oxides. Certain compounds may exist in multiple crystalline,co-crystalline, or amorphous forms. Compounds of Formula (I) includepharmaceutically acceptable salts thereof, pharmaceutically acceptablesolvates of the free acid form of any of the foregoing, as well ascrystalline or co-crystalline forms of any of the foregoing.

In general, all physical forms are equivalent for the uses contemplatedherein and are intended to be within the scope of the presentdisclosure. Further, it should be understood, when partial structures ofthe compounds are illustrated, that an asterisk indicates the point ofattachment of the partial structure to the rest of the molecule.

“Corresponding α-amino acid” refers to an α-amino acid of Formula (III)having the same R⁴, R⁵, and R⁶ groups as the α-amino acid prodrug ofFormula (I).

“Cycloalkoxycarbonyl,” by itself or as part of another substituent,refers to the radical —C(O)OR⁵² where R⁵² represents an cycloalkyl groupas defined herein. Examples of cycloalkoxycarbonyl groups include, butare not limited to, cyclobutyloxycarbonyl, cyclohexyloxycarbonyl, andthe like.

“Cycloalkyl,” by itself or as part of another substituent, refers to asaturated or partially unsaturated cyclic alkyl radical. Where aspecific level of saturation is intended, the nomenclature“cycloalkanyl” or “cycloalkenyl” is used. Examples of cycloalkyl groupsinclude, but are not limited to, groups derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane, and the like. In certainembodiments, a cycloalkyl group is C₃₋₁₀ cycloalkyl, and in certainembodiments, C₃₋₇ cycloalkyl.

“Cycloheteroalkyl,” by itself or as part of another substituent, refersto a saturated or partially unsaturated cyclic alkyl radical in whichone or more carbon atoms (and any associated hydrogen atoms) areindependently replaced with the same or different heteroatom. Examplesof heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Where a specific level of saturation isintended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl”is used. Examples of cycloheteroalkyl groups include, but are notlimited to, groups derived from epoxides, azirines, thiiranes,imidazolidine, morpholine, piperazine, piperidine, pyrazolidine,pyrrolidine, quinuclidine, and the like.

“Dialkylamino,” by itself or as part of another substituent refers tothe radical —NR⁴³R⁴⁴ where R⁴³ and R⁴⁴ are independently chosen fromalkyl, cycloalkyl, cycloheteroalkyl, arylalkyl, heteroalkyl, andheteroarylalkyl, or R⁴³ and R⁴⁴ together with the nitrogen to which theyare bonded form a cycloheteroalkyl ring.

“1,1-Cyclopropane ring” refers to a moiety having the structuralformula:

wherein the dashed bonds indicate the positions to which the1,1-cyclopropane ring is bonded. In certain embodiments, one or more ofthe hydrogen atoms bonded to the 1,1-cyclopropane ring is independentlysubstituted with a substituent group chosen from halogen, C₁₋₃ alkyl,—OH, —NH₂, —SH, C₁₋₃ alkoxy, C₁₋₃ acyl, C₁₋₃ thioalkyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylamino, and C₁₋₃ dialkylamino.

“Disease” refers to a disease, disorder, condition, symptom, orindication.

“Heteroalkyl,” by itself or as part of another substituent, refers to analkyl group in which one or more of the carbon atoms (and any associatedhydrogen atoms) are independently replaced with the same or differentheteroatomic groups. Examples of heteroatomic groups include, but arenot limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR⁷⁰R⁷¹—, ═N—N═, —N═N—,—N═N—NR⁷²R⁷³, —PR⁷⁴—, —P(O)₂—POR⁷⁵—, —O—P(O)₂—SO—, —SO₂—, —SnR⁷⁶R⁷⁷—,and the like, where R⁷⁰, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁶, and R⁷⁷ areindependently chosen from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. Where aspecific level of saturation is intended, the nomenclature“heteroalkanyl,” “heteroalkenyl,” or “heteroalkynyl” is used.

“Heteroaryl,” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring system.Heteroaryl encompasses multiple ring systems having at least oneheteroaromatic ring fused to at least one other ring, which may bearomatic or non-aromatic. Heteroaryl encompasses 5- to 7-memberedaromatic, monocyclic rings containing one or more, for example, from 1to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N,O, and S, with the remaining ring atoms being carbon; and bicyclicheterocycloalkyl rings containing one or more, for example, from 1 to 4,or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O,and S, with the remaining ring atoms being carbon and wherein at leastone heteroatom is present in an aromatic ring. For example, heteroarylincludes a 5- to 7-membered heteroaromatic ring fused to a 5- to7-membered cycloalkyl ring. For such fused, bicyclic heteroaryl ringsystems wherein only one of the rings contains one or more heteroatoms,the point of attachment may be at the heteroaromatic ring or thecycloalkyl ring. In certain embodiments, when the total number of N, S,and O atoms in the heteroaryl group exceeds one, the heteroatoms are notadjacent to one another. In certain embodiments, the total number of N,S, and O atoms in the heteroaryl group is not more than two. In certainembodiments, the total number of N, S, and O atoms in the aromaticheterocycle is not more than one. Heteroaryl does not encompass oroverlap with aryl as defined herein.

Examples of heteroaryl groups include, but are not limited to, groupsderived from acridine, arsindole, carbazole, β-carboline, chromane,chromene, cinnoline, furan, imidazole, indazole, indole, indoline,indolizine, isobenzofuran, isochromene, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like. In certain embodiments, a heteroarylgroup is a 5- to 20-membered heteroaryl, and in certain embodiments a 5-to 10-membered heteroaryl. In certain embodiments, heteroaryl groups arethose derived from thiophene, pyrrole, benzothiophene, benzofuran,indole, pyridine, quinoline, imidazole, oxazole, and pyrazine.

“Heteroarylalkyl,” by itself or as part of another substituent, refersto an acyclic alkyl radical in which one of the hydrogen atoms bonded toa carbon atom, typically a terminal or sp³ carbon atom, is replaced witha heteroaryl group. Where specific alkyl moieties are intended, thenomenclature “heteroarylalkanyl,” “heteroarylalkenyl,” and“heteroarylalkynyl” is used. In certain embodiments, a heteroarylalkylgroup is a 6- to 30-membered heteroarylalkyl, e.g., the alkanyl,alkenyl, or alkynyl moiety of the heteroarylalkyl is 1- to 10-memberedand the heteroaryl moiety is a 5- to 20-membered heteroaryl, and incertain embodiments, 6- to 20-membered heteroarylalkyl, e.g., thealkanyl, alkenyl, or alkynyl moiety of the heteroarylalkyl is 1- to8-membered and the heteroaryl moiety is a 5- to 12-membered heteroaryl.

“Neuropsychiatric” and/or “neurodegenerative disorders” includepsychotic disorders such as schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, drug-induced psychoticdisorder, and illness associated with psychosis (e.g., major depression,bipolar disorder, and post-traumatic stress syndrome); cognitivedisorders including dementia (e.g., associated with Alzheimer's disease,Parkinson's disease, Huntington's disease, HIV, Pick's Disease, andCreutzfeldt-Jakob disease), amnestic disorders, and age-relatedcognitive decline; anxiety disorders including generalized anxietydisorder, obsessive-compulsive disorder, social phobia, and panicattack; mood disorders (e.g., depression, seasonal depression,postpartum depression, premenstrual syndrome, and premenstrual dysphoricdisorder); attention disorders including attention-deficit hyperactivitydisorder; autism; and movement disorders (e.g., Parkinsonism, akinesias,akathisias, and dyskinesias including tardive dyskinesia, dystonia,spasticity, epilepsy, and Tourette's syndrome), the diagnosis of whichcan be made with reference to the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR, Fourth Edition, TextRevision, American Psychiatric Association, Washington D.C., 2000).

“Parent aromatic ring system” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π (pi) electron system.Included within the definition of “parent aromatic ring system” arefused ring systems in which one or more of the rings are aromatic andone or more of thec rings are saturated, partially saturated, orunsaturated, for example, fluorene, indane, indene, phenalene, etc.Examples of parent aromatic ring systems include, but are not limitedto, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexylene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene, and the like.

“Parent heteroaromatic ring system” refers to a parent aromatic ringsystem in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Examples of heteroatoms to replace the carbon atoms include, but are notlimited to, N, P, O, S, Si, etc. Specifically included within thedefinition of “parent heteroaromatic ring systems” are fused ringsystems in which one or more of the rings are aromatic and one or moreof the rings are saturated, partially saturated, or unsaturated, suchas, for example, arsindole, benzodioxan, benzofuran, chromane, chromene,indole, indoline, xanthene, etc. Examples of parent heteroaromatic ringsystems include, but are not limited to, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

“Patient” includes mammals, such as for example, humans.

“Pharmaceutical composition” refers to at least one compound of Formula(I) and a pharmaceutically acceptable vehicle, with which the compoundis to be administered to a patient.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of a federal or a state government, listed in the U.S.Pharmacopoeia or listed other generally recognized pharmacopoeia for usein mammals, including humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include: (1) acid addition salts, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; and (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthmetal ion, or an aluminum ion; or coordinates with an organic base suchas ethanolamine, diethanolamine, triethanolamine, N-methylglucamine andthe like. In certain embodiments, the salt is the hydrochloride salt,and in certain embodiments the salt is the sodium salt.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which a compoundof Formula (I) may be administered to a patient and which does notdestroy the pharmacological activity thereof, and which is nontoxic whenadministered in doses sufficient to provide a therapeutically effectiveamount of the compound.

Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently, although not necessarily, pharmacologically inactive untilconverted to the parent drug. Prodrugs may be obtained by bonding apromoiety (defined herein) typically via a functional group, to a drug.

“Promoiety” refers to a group bonded to a drug, typically to afunctional group of the drug, via bond(s) that are cleavable underspecified conditions of use. The bond(s) between the drug and promoietymay be cleaved by enzymatic or non-enzymatic means. Under the conditionsof use, for example following administration to a patient, the bond(s)between the drug and promoiety may be cleaved to release the parentdrug. The cleavage of the promoiety may proceed spontaneously, such asvia a hydrolysis reaction, or it may be catalyzed or induced by anotheragent, such as by an enzyme, by light, by acid, or by a change of orexposure to a physical or environmental parameter, such as a change oftemperature, pH, etc. The agent may be endogenous to the conditions ofuse, such as an enzyme present in the systemic circulation to which theprodrug is administered or the acidic conditions of the stomach, or theagent may be supplied exogenously. In certain embodiments, the drug isan α-amino acid of Formula (III) and the promoiety is anacyloxyalkyloxycarbonyl group having the structure:

where R¹, R², and R³ are defined herein.

“Protecting group” refers to a group of atoms, that when bonded to areactive-functional group in a molecule, masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Wuts and Greene et al., “Protective Groups in OrganicSynthesis,” John Wiley and Sons, 4th ed, 2006, and Harrison et al.,“Compendium of Synthetic Organic Methods,” Vols. 1-11, John Wiley andSons, 1971-2003. Representative amino protecting groups include, but arenot limited to, formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl(TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substitutedtrityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), and the like. Representative hydroxyprotecting groups include, but are not limited to, those where thehydroxy group is either acylated or alkylated such as benzyl, ahd tritylethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers, and allyl ethers.

“Solvate” refers to a molecular complex of a compound with one or moresolvent molecules in a stoichiometric or non-stoichiometric amount. Suchsolvent molecules are those commonly used in the pharmaceutical arts,e.g., water, ethanol, and the like. A molecular complex of a compound ormoiety of a compound and a solvent can be stabilized by non-covalentintra-molecular forces such as, electrostatic forces, van der Waalsforces, and/or hydrogen bonds. The term “hydrate” refers to a complex inwhich the one or more solvent molecules are water including monohydratesand hemi-hydrates.

“Substantially one diastereomer” refers to a compound containing two ormore stereogenic centers such that the diastereomeric excess (d.e.) ofthe compound is greater than or equal to 90%. In certain embodiments,the d.e. is, for example, greater than or equal to 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, and 99%.

“Substantially one enantiomer” refers to a compound containing onestereogenic center such that the enantiomeric excess (e.e.) of thecompound is at least 90%. In certain embodiments, the e.e. is, forexample, greater than or equal to 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, and 99%.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or different substituent(s).Examples of substituents include, but are not limited to, —X, —R⁶⁰, —O⁻,═O, —OR⁶⁰, —SR⁶⁰, —S⁻, S, —NR⁶⁰R⁶¹, ═NR⁶⁰, —CX₃, —CN, —CF₃, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂O—, —S(O)₂OH, —S(O)₂R⁶¹, —OS(O₂)O—,—OS(O)₂R⁶⁰, —P(O)(O—)₂, —P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰,—C(S)R⁶¹, —C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹, —C(O)O, (S)OR⁶⁰, —NR⁶²C(O)NR⁶R⁶,—NR⁶²C(S)NR⁶⁰R⁶¹, —NR⁶²C(NR⁶³)NR⁶⁰R⁶¹, —C(NR⁶²)NR⁶OR⁶¹, —S(O)₂, NR⁶OR⁶¹,—NR⁶³S(O)₂R⁶⁰, —NR⁶³C(O)R⁶⁰, and —S(O)R⁶⁰ where each X is independentlya halogen; each R⁶⁰ and R⁶¹ are independently chosen from hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,substituted arylalkyl, heteroarylalkyl, and substituted heteroarylalkyl,or R⁶⁰ and R⁶¹, together with the nitrogen atom to which they arebonded, form a ring chosen from a cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, and substituted heteroaryl ring; and eachR⁶² and R⁶³ are independently chosen from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,and substituted heteroarylalkyl, or R⁶² and R⁶³, together with the atomto which they are bonded, form one or more rings chosen from acycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, andsubstituted heteroaryl ring. In certain embodiments, a tertiary amine oraromatic nitrogen may be substituted with one or more oxygen atoms toform the corresponding nitrogen oxide.

In certain embodiments of compounds of Formula (I), each substituentgroup is independently chosen from halogen, C₁₋₃ alkyl, —OH, —NH₂, —SH,C₁₋₃ alkoxy, C₁₋₃ acyl, C₁₋₃ thioalkyl, C₁₋₃ alkoxycarbonyl, C 3alkylamino, and C₁₋₃ dialkylamino.

“Sulfonamido,” by itself or as part of another substituent refers to aradical —NR⁵³S(O)₂R⁵⁴, where R⁵³ is chosen from alkyl, substitutedalkyl, cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, arylalkyl,heteroalkyl, heteroaryl, and heteroarylalkyl; and R⁵⁴ is chosen fromhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,heteroalkyl, heteroaryl, and heteroarylalkyl, as defined herein.Examples of sulfonamido groups include, but are not limited to,methanesulfonamido, benzenesulfonamido, and p-toluenesulfonamido.

“Thioalkyl,” by itself or as part of another substituent, refers to aradical —SR⁴¹ where R⁴¹ is alkyl, as defined herein.

“Treating” or “treatment” of a disease refers to arresting orameliorating a disease, disorder, or at least one of the clinicalsymptoms of a disease or disorder. In certain embodiments, “treating” or“treatment” refers to arresting or ameliorating at least one physicalparameter of the disease or disorder, which may or may not bediscernible by the patient. In certain embodiments, “treating” or“treatment” refers to inhibiting or controlling the disease or disorder,either physically (e.g., stabilization of a discernible symptom),physiologically (e.g., stabilization of a physical parameter), or both.In certain embodiments, “treating” or “treatment” refers to delaying, insome cases indefinitely, the onset of a disease or disorder. In certainembodiments, “treating” or “treatment” refers to reducing the risk ofacquiring a disease, disorder, or a clinical symptom of the disease ordisorder.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, ordisorder, or at least one of the clinical symptoms of a disease ordisorder, is sufficient to affect such treatment of the disease,disorder, or symptom. The “therapeutically effective amount” may varydepending, for example, on the compound, the disease, disorder, and/orsymptoms of the disease, severity of the disease, disorder, and/orsymptoms of the disease, the age, weight, and/or health of the patientto be treated, and the judgment of the prescribing physician. Anappropriate amount in any given instance may be readily ascertained bythose skilled in the art or capable of determination by routineexperimentation. Reference is now be made in detail to particularembodiments of compounds and methods. The disclosed embodiments are notintended to be limiting of the claims. To the contrary, the claims areintended to cover all alternatives, modifications, and equivalents.

Compounds

Certain embodiments of the present disclosure provide compounds ofFormula (I):

pharmaceutically acceptable salts of any of the foregoing, and apharmaceutically acceptable solvates of any of the foregoing, wherein:

R¹ is chosen from acyl, substituted acyl, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R² and R³ are independently chosen from hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl, or R² and R³ together with the carbon atomto which they are bonded form a ring chosen from a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, and substitutedcycloheteroalkyl ring;

R⁴ is chosen from hydrogen and methyl;

R⁵ is chosen from hydrogen, methyl, and hydroxymethyl; and

R⁶ is hydrogen, or R⁵ and R⁶ together with the carbon atom to which theyare bonded, form a ring chosen from a 1,1-cyclopropane ring andsubstituted 1,1-cyclopropane ring.

In certain embodiments of the compounds of Formula (I), each substituentgroup is independently chosen from halogen, C₁₋₃ alkyl, —OH, —NH₂, —SH,C₁₋₃ alkoxy, C₁₋₃ acyl, C₁₋₃ thioalkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkylamino, and C₁₋₃ dialkylamino.

In certain embodiments of the compounds of Formula (I), R⁴ is hydrogen,R⁵ is hydroxymethyl, and R⁶ is hydrogen. In certain embodiments of thecompounds of Formula (I), R⁴ is hydrogen, R⁵ is methyl, and R⁶ ishydrogen. In certain embodiments of the compounds of Formula (I), R⁴ ishydrogen, and R⁵ and R⁶ together with the carbon atom to which they arebonded form a 1,1-cyclopropane ring. In certain embodiments of thecompounds of Formula (I), R⁴ is methyl, R⁵ is hydrogen, and R⁶ ishydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₀ aryl, substituted C₆₋₁₀aryl, C₃₋₇ cycloalkyl, substituted C₃₋₇ cycloalkyl, C₆₋₁₀ arylalkyl, andC₆₋₁₀ substituted arylalkyl. In certain embodiments of the compounds ofFormula (I) wherein R¹ is chosen from C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, substitutedC₃₋₇ cycloalkyl, C₆₋₁₀ arylalkyl, and C₆₋₁₀ substituted arylalkyl, eachsubstituent group is independently chosen from halogen, C₁₋₃ alkyl, —OH,—NH₂, —SH, C₁₋₃ alkoxy, C₁₋₃ acyl, C₁₋₃ thioalkyl, C₁₋₃ alkoxycarbonyl,C₁₋₃ alkylamino, and C₁₋₃ dialkylamino.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom C₁₋₄ alkyl, phenyl, substituted phenyl, cyclohexyl, substitutedcyclohexyl, styryl, and substituted styryl. In certain embodiments ofthe compounds of Formula (I) wherein R¹ is chosen from C₁₋₄ alkyl,phenyl, substituted phenyl, cyclohexyl, substituted cyclohexyl, styryl,and substituted styryl, each substituent group is independently chosenfrom halogen, C₁₋₃ alkyl, —OH, —NH₂, —SH, C₁₋₃ alkoxy, C₁₋₃ acyl, C₁₋₃thioalkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylamino, and C₁₋₃ dialkylamino.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl.

In certain embodiments of the compounds of Formula (I), R² and R³ areindependently chosen from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, and substitutedC₃₋₇ cycloalkyl. In certain embodiments of the compounds of Formula (I)wherein R² and R³ are independently chosen from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₃₋₇cycloalkyl, and substituted C₃₋₇ cycloalkyl, each substituent group isindependently chosen from halogen, C₁₋₃ alkyl, —OH, —NH₂, —SH, C₁₋₃alkoxy, C₁₋₃ acyl, C₁₋₃ thioalkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylamino,and C₁₋₃ dialkylamino.

In certain embodiments of the compounds of Formula (I), R² and R³ areindependently chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl,phenyl, and cyclohexyl.

In certain embodiments of the compounds of Formula (I), R² is hydrogen,and R³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl,phenyl, and cyclohexyl.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₀ aryl, substituted C₆₋₁₀aryl, C₃₋₇ cycloalkyl, substituted C₃₋₇ cycloalkyl, C₆₋₁₀ arylalkyl, andC₆₋₁₀ substituted arylalkyl, and R² and R³ are independently chosen fromhydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₀ aryl, substitutedC₆₋₁₀ aryl, C₃₋₇ cycloalkyl, and substituted C₃₋₇ cycloalkyl. In certainembodiments of a compound of Formula (I) wherein R¹ is chosen from C₁₋₆alkyl, substituted C₁₋₆ alkyl, C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₃₋₇cycloalkyl, substituted C₃₋₇ cycloalkyl, C₆₋₁₀ arylalkyl, and C₆₋₁₀substituted arylalkyl, and R² and R³ are independently chosen fromhydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₀ aryl, substitutedC₆₋₁₀ aryl, C₃₋₇ cycloalkyl, and substituted C₃₋₇ cycloalkyl, eachsubstituent group is independently chosen from halogen, C₁₋₃ alkyl, —OH,—NH₂, —SH, C₁₋₃ alkoxy, C₁₋₃ acyl, C₁₋₃ thioalkyl, C₁₋₃ alkoxycarbonyl,C₁₋₃ alkylamino, and C₁₋₃ dialkylamino.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, andR³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl,and cyclohexyl.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is hydrogen, R⁴ is hydrogen, R⁵ is hydroxymethyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is methyl, R⁴ is hydrogen, R⁵ is hydroxymethyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is ethyl, R⁴ is hydrogen, R⁵ is hydroxymethyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is n-propyl, R⁴ is hydrogen, R⁵ is hydroxymethyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is isopropyl, R⁴ is hydrogen, R⁵ is hydroxymethyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is phenyl, R⁴ is hydrogen, R⁵ is hydroxymethyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is cyclohexyl, R⁴ is hydrogen, R⁵ is hydroxymethyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is hydrogen, R⁴ is hydrogen, R⁵ is methyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is methyl, R⁴ is hydrogen, R⁵ is methyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is ethyl, R⁴ is hydrogen, R⁵ is methyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is n-propyl, R⁴ is hydrogen, R⁵ is methyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is isopropyl, R⁴ is hydrogen, R⁵ is methyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is phenyl, R⁴ is hydrogen, R⁵ is methyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is cyclohexyl, R⁴ is hydrogen, R⁵ is methyl, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is hydrogen, R⁴ is hydrogen, and R⁵ and R⁶ together with the carbon atomto which they are bonded form a 1,1-cyclopropane ring.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is methyl, R⁴ is hydrogen, and R⁵ and R⁶ together with the carbon atomto which they are bonded form a 1,1-cyclopropane ring.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is ethyl, R⁴ is hydrogen, and R⁵ and R⁶ together with the carbon atom towhich they are bonded form a 1,1-cyclopropane ring.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is n-propyl, R⁴ is hydrogen, and R⁵ and R⁶ together with the carbon atomto which they are bonded form a 1,1-cyclopropane ring.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is isopropyl, R⁴ is hydrogen, and R⁵ and R⁶ together with the carbonatom to which they are bonded form a 1,1-cyclopropane ring.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is phenyl, R⁴ is hydrogen, and R⁵ and R⁶ together with the carbon atomto which they are bonded form a 1,1-cyclopropane ring.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, and cyclohexyl, and styryl, R² is hydrogen,R³ is cyclohexyl, R⁴ is hydrogen, and R⁵ and R⁶ together with the carbonatom to which they are bonded form a 1,1-cyclopropane ring.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is hydrogen, R⁴ is methyl, R⁵ is hydrogen, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is methyl, R⁴ is methyl, R⁵ is hydrogen, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is ethyl, R⁴ is methyl, R⁵ is hydrogen, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is n-propyl, R⁴ is methyl, R⁵ is hydrogen, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is isopropyl, R⁴ is methyl, R⁵ is hydrogen, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is phenyl, R⁴ is methyl, R⁵ is hydrogen, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is cyclohexyl, R⁴ is methyl, R⁵ is hydrogen, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, R³is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, andcyclohexyl, R⁴ is hydrogen, R⁵ is chosen from methyl and hydroxymethyl,and R⁶ is hydrogen, or R⁵ and R⁶ together with the carbon atom to whichthey are bonded form a 1,1-cyclopropane ring.

In certain embodiments of the compounds of Formula (I), R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl, R² is hydrogen, andR³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl,and cyclohexyl, R⁴ is methyl, R⁵ is hydrogen, and R⁶ is hydrogen.

In certain embodiments of the compounds of Formula (I) wherein R⁴ ishydrogen, R⁵ is hydroxymethyl, and R⁶ is hydrogen; R¹ is chosen fromC₁₋₄ alkyl, phenyl, substituted phenyl, cyclohexyl, and substitutedcyclohexyl; R² is chosen from hydrogen, and C₁₋₄ alkyl; and R³ ishydrogen.

In certain embodiments of the compounds of Formula (I) wherein R⁴ ishydrogen, R⁵ is hydroxymethyl, and R⁶ is hydrogen; the compound ischosen from:

-   (2R)-3-hydroxy-2-{[2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}propanoic    acid;-   (2R)-3-hydroxy-2-{[(2-methylpropanoyloxy)methoxy]carbonylamino}propanoic    acid;-   (2R)-3-hydroxy-2-[(pentanoyloxyethoxy)carbonylamino]propanoic acid;-   (2R)-2-[(butanoyloxyethoxy)carbonylamino]-3-hydroxypropanoic acid;-   (2R)-3-hydroxy-2-{[(2-methylpropanoyloxy)ethoxy]carbonylamino}propanoic    acid;-   (2R)-3-hydroxy-2-[(phenylcarbonyloxyethoxy)carbonylamino]propanoic    acid;-   (2R)-2-[(cyclohexylcarbonyloxyethoxy)carbonylamino]-3-hydroxypropanoic    acid;-   (2R)-3-hydroxy-2-{[(3-methylbutanoyloxy)ethoxy]carbonylamino}propanoic    acid;-   (2R)-3-hydroxy-2-{[(2-methylphenylcarbonyloxy)ethoxy]carbonylamino}propanoic    acid;-   (2R)-2-{[(2,2-dimethylpropanoyloxy)ethoxy]carbonylamino}-3-hydroxypropanoic    acid;-   (2R)-2-[(1-cyclohexylcarbonyloxy-2-methylpropoxy)carbonylamino]-3-hydroxypropanoic    acid;-   (2R)-3-hydroxy-2-[(2-methyl-1-phenylcarbonyloxypropoxy)carbonylamino]propanoic    acid;-   (2R)-2-[(heptanoyloxyethoxy)carbonylamino]-3-hydroxypropanoic acid;

a pharmaceutically acceptable salt of any of the foregoing, and apharmaceutically acceptable solvate of any of the foregoing.

In certain embodiments of the compounds of Formula (I) wherein R⁴ ishydrogen, R⁵ and R⁶ together with the carbon atom to which they arebonded form a 1,1-cyclopropane ring; R¹ is chosen from C₁₋₆ alkyl,phenyl, substituted phenyl, cyclohexyl, substituted cyclohexyl, C₇₋₉phenylalkyl, and adamantyl; R² is chosen from hydrogen and C₁₋₄ alkyl;and R³ is hydrogen.

In certain embodiments of the compounds of Formula (I) wherein R⁴ ishydrogen, R⁵ and R⁶ together with the carbon atom to which they arebonded form a 1,1-cyclopropane ring; the compound is chosen from:

-   1-(1-isobutyryloxy-ethoxycarbonylamino)-cyclopropanecarboxylic acid;-   1-(1-Isobutyryloxy-2-methyl-propoxycarbonylamino)-cyclopropanecarboxylic    acid;-   1-{[(2-methylphenylcarbonyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic    acid;-   1-[(phenylcarbonyloxyethoxy)carbonylamino]cyclopropanecarboxylic    acid;-   1-[1-(3-methyl-butyryloxy)-ethoxycarbonylamino]-cyclopropanecarboxylic    acid;-   1-[1-(2,2-dimethyl-propionyloxy)-ethoxycarbonylamino]-cyclopropanecarboxylic    acid;-   1-(1-butyryloxy-ethoxycarbonylamino)-cyclopropanecarboxylic acid;-   (1-pentanoyloxy-ethoxycarbonylamino)-cyclopropanecarboxylic acid;-   1-isobutyryloxymethoxycarbonylaminocyclopropanecarboxylic acid;-   1-[(cyclohexylcarbonyloxyethoxy)carbonylamino]cyclopropanecarboxylic    acid;-   1-[(1-cyclohexylcarbonyloxy-2-methylpropoxy)carbonylamino]cyclopropanecarboxylic    acid;-   1-[(2-methyl-1-phenylcarbonyloxypropoxy)carbonylamino]cyclopropanecarboxylic    acid;-   1-[(heptanoyloxyethoxy)carbonylamino]cyclopropanecarboxylic acid;-   1-{[(3,4-dimethoxyphenylcarbonyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic    acid;-   1-{[(4-phenylbutanoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic    acid;-   1-{[((2E)-3-phenylprop-2-enoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic    acid;-   1-{[2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}sodium    cyclopropanoate;-   1-{[(2-phenylacetyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic    acid;-   1-{[(4-methylphenylcarbonyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic    acid;-   1-[(adamantanecarbonyloxyethoxy)carbonylamino]cyclopropanecarboxylic    acid;-   1-{[(3-phenylpropanoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic    acid;-   1-{[2-methyl-1-(3-phenylpropanoyloxy)propoxy]carbonylamino}cyclopropanecarboxylic    acid;

a pharmaceutically acceptable salt of any of the foregoing, and apharmaceutically acceptable solvate of any of the foregoing.

In certain embodiments of the compounds of Formula (I) wherein R⁴ ismethyl, R⁵ is hydrogen, and R⁶ is hydrogen; R¹ is chosen from C₁₋₆alkyl, phenyl, substituted phenyl, cyclohexyl, and substitutedcyclohexyl; R² is chosen from hydrogen, C₁₋₄ alkyl, phenyl, substitutedphenyl, cyclohexyl, and substituted cyclohexyl; and R³ is hydrogen.

In certain embodiments of the compounds of Formula (I) wherein R⁴ ismethyl, R⁵ is hydrogen, and R⁶ is hydrogen; the compound is chosen from:

-   2-{N-methyl[2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}acetic    acid;-   2-{N-methyl[(2-methylpropanoyloxy)ethoxy]carbonylamino}acetic acid;-   2-{N-methyl[(2-methylphenylcarbonyloxy)ethoxy]carbonylamino}acetic    acid;-   2-[N-methyl(phenylcarbonyloxyethoxy)carbonylamino]acetic acid;-   2-{[(2,2-dimethylpropanoyloxy)ethoxy]-N-methylcarbonylamino}acetic    acid;-   2-[(cyclohexylcarbonyloxyethoxy)-N-methylcarbonylamino]acetic acid;-   2-[N-methyl(pentanoyloxyethoxy)carbonylamino]acetic acid;-   2-[(butanoyloxyethoxy)-N-methylcarbonylamino]acetic acid;-   2-{N-methyl[(3-methylbutanoyloxy)ethoxy]carbonylamino}acetic acid;-   2-{N-methyl[(2-methylpropanoyloxy)methoxy]carbonylamino}acetic acid;-   2-[N-methyl(phenylphenylcarbonyloxymethoxy)carbonylamino]acetic    acid;-   2-[(1-cyclohexylcarbonyloxy-2-methylpropoxy)-N-methylcarbonylamino]acetic    acid;-   2-[N-methyl(2-methyl-1-phenylcarbonyloxypropoxy)carbonylamino]acetic    acid;-   2-[(heptanoyloxyethoxy)-N-methylcarbonylamino]acetic acid;

a pharmaceutically acceptable salt of any of the foregoing, and apharmaceutically acceptable solvate of any of the foregoing.

In certain embodiments, the acyloxyalkyl carbamate prodrugs of Formula(I) are acyloxylalkyl carbamate prodrugs of D-serine, D-alanine,1-aminocyclopropanecarboxylic acid, or sarcosine.

In certain embodiments, the acyloxyalkyl carbamate prodrugs of Formula(I) are colonically absorbable, e.g., the acyloxyalkyl carbamateprodrugs of Formula (I) are colonically absorbable forms of thecorresponding α-amino acids. In certain embodiments, the acyloxyalkylcarbamate prodrugs of Formula (I) are a colonically absorbable form ofan α-amino acid chosen from D-serine, D-alanine,1-aminocyclopropanecarboxylic acid, and sarcosine.

In certain embodiments, the colonically absorbable forms of the α-aminoacids provide an α-amino acid plasma AUC in a patient following colonicadministration that is at least two times greater than the α-amino acidplasma AUC in the patient following colonic administration of anequivalent dose of the α-amino acid itself in an equivalent dosage form.

In certain embodiments, the compounds of Formula (I), when orallyadministered, provide an oral bioavailability of the correspondingα-amino acids in the plasma of a patient that is at least ten timesgreater than the oral bioavailability of the α-amino acid following oraladministration of the α-amino acids themselves in an equivalent dosageform.

Synthesis

Methods for synthesis of acyloxyalkyl carbamate derivatives of aminesare known in the art (see, for example, Alexander et al., U.S. Pat. No.4,426,391; Alexander, U.S. Pat. No. 4,760,057; Lund, U.S. Pat. No.5,401,868; Alexander, U.S. Pat. No. 4,760,057; Saari et al., EuropeanPatent 0416689B1; Mulvihill et al., Tetrahedron Lett. 2001, 7751-7754;Sun et al., Bioorg. Med. Chem. Lett. 2001, 11, 1875-1879; Sun et al.,Bioorg. Med. Chem. Lett. 2001, 11, 3055-3059; Chen et al., PCTInternational Publication No. WO 01/05813; Mulvihill et al., Synthesis2002, 3, 365-370; Gallop et al., U.S. Pat. No. 6,927,036; Raillard etal., U.S. Pat. No. 7,232,924; Bhat et al., U.S. Application PublicationNo. 2005/0070715; and Gallop et al., U.S. Pat. No. 7,227,028).

General synthetic methods useful in the synthesis of the compoundsdescribed herein are also available in the art (e.g., Wuts and Greene,“Protective Groups in Organic Synthesis,” John Wiley & Sons, 4th ed.2006; Harrison et al., “Compendium of Organic Synthetic Methods,” Vols.1-11, John Wiley & Sons 1971-2003; Larock “Comprehensive OrganicTransformations,” John Wiley & Sons, 2nd ed. 2000; and Paquette,“Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons,11th ed. 2003).

Starting materials useful for preparing compounds provided by thepresent disclosure and intermediates thereof, and/or practicing themethods described herein are commercially available or can be preparedby well-known synthetic methods. Other methods for synthesis of theprodrugs of the present disclosure are either described in the art orwill be readily apparent to those skilled in the art in view of thereferences provided herein and may be used to synthesize the compoundsdescribed herein. Accordingly, the methods presented herein areillustrative rather than comprehensive.

A method of synthesizing compounds of Formula (I), illustrated in Scheme1, involves the reaction of an α-amino acid compound of Formula (III)with a 1-(acyloxy)-alkyl N-hydroxysuccinimidyl carbonate compound ofFormula (II), as described in the co-pending application Gallop et al.,U.S. Pat. No. 7,227,028, which is incorporated by reference herein inits entirety:

wherein,

R¹ is chosen from acyl, substituted acyl, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R² and R³ are independently chosen from hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl; or R² and R³, together with the carbon atomto which they are bonded, form a ring chosen from a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, and substitutedcycloheteroalkyl ring;

R⁴ is chosen from hydrogen and methyl;

R⁵ is chosen from hydrogen, methyl, and hydroxymethyl;

R⁶ is hydrogen, or R⁵ and R⁶, together with the carbon atom to whichthey are bonded, form a 1,1-cyclopropane ring; and

R⁷ and R⁸ are independently chosen from hydrogen, acylamino, acyloxy,alkoxycarbonylamino, alkoxycarbonyloxy, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl,substituted arylalkyl, carbamoyloxy, dialkylamino, heteroaryl,substituted heteroaryl, hydroxy, and sulfonamido, or R⁷ and R⁸, togetherwith the atoms to which they are bonded, form a ring chosen from asubstituted cycloalkyl, substituted cycloheteroalkyl, and substitutedaryl ring.

In certain embodiments of the method of Scheme I for synthesizing acompound of Formula (I), each of R⁷ and R⁸ in the compound of Formula(II) is hydrogen.

In certain embodiments of the method described in Scheme I forsynthesizing a compound of Formula (I), R² and R³ in the compound ofFormula (II) are different, such that the carbon atom to which thesesubstituents are bonded is a stereogenic center.

In certain embodiments of methods of synthesizing a compound of Formula(I), R² and R³ in the compound of Formula (I) are different and thecompound of Formula (I) exists as substantially one enantiomer.

In certain embodiments of methods of synthesizing a compound of Formula(I), R² and R³ in the compound of Formula (I) are different and thecompound of Formula (I) exists as substantially one diastereomer.

In certain embodiments of the method of Scheme I for synthesizing acompound of Formula (I), each of R⁷ and R⁸ in the compound of Formula(II) is benzoyloxy, the stereochemistry at the carbon to which R⁷ isbonded is of the R-configuration, and the stereochemistry at the carbonto which R⁸ is bonded is of the R-configuration. In certain embodimentsof the method of Scheme I for synthesizing a compound of Formula (I),each of R⁷ and R⁸ in the compound of Formula (II) is benzoyloxy, thestereochemistry at the carbon to which R⁷ is bonded is of theS-configuration, and the stereochemistry at the carbon to which R⁸ isbonded is of the S-configuration.

In certain embodiments, the method of Scheme 1 is carried out in asolvent. Solvents that may be used include, but are not limited to,acetone, acetonitrile, dichloromethane, dichloroethane, chloroform,toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide,N-methylpyrrolidinone, dimethyl sulfoxide, pyridine, ethyl acetate,methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butanol,water, and combinations of any of the foregoing. In certain embodiments,the solvent may be acetone, acetonitrile, dichloromethane, toluene,tetrahydrofuran, pyridine, methyl tert-butyl ether, methanol, ethanol,isopropanol, water, and combinations of any of the foregoing. In certainembodiments, the solvent may be a combination of acetonitrile and water.In certain embodiments, the solvent may be a combination of acetonitrileand water, with a volume ratio of acetonitrile to water ranging fromabout 1:5 to about 5:1. In certain embodiments, the solvent may be acombination of methyl tert-butyl ether and water. In certainembodiments, the solvent may be a combination of methyl tert-butyl etherand water, with a volume ratio of methyl tert-butyl ether to waterranging from about 2:1 to about 20:1. In certain embodiments, thesolvent is a combination of methyl tert-butyl ether and water, whereinthe methyl tert-butyl ether contains from about 10% to about 50% acetoneby volume. In certain embodiments, the solvent is dichloromethane,water, or a combination thereof. In certain embodiments, the solvent isa biphasic combination of dichloromethane and water. In certainembodiments, the solvent is a biphasic combination of dichloromethaneand water containing from about 0.001 equivalents to about 0.1equivalents of a phase transfer catalyst. In certain embodiments, thephase transfer catalyst is a tetraalkylammonium salt, and in certainembodiments, the phase transfer catalyst is a tetrabutylammonium salt.

The method of Scheme 1 may be carried out a temperature ranging fromabout −20° C. to about 40° C. In certain embodiments, the temperatureranges from about −20° C. to about 25° C. In certain embodiments, thetemperature ranges from about 0° C. to about 25° C. In certainembodiments, the temperature ranges from about 25° C. to about 40° C.

In certain embodiments of the method of Scheme 1, the reaction isperformed in the absence of a base.

In certain embodiments of the method of Scheme 1, the reaction isperformed in the presence of an inorganic base. In certain embodiments,the reaction is performed in the presence of an alkali metal bicarbonateor alkali metal carbonate salt. In certain embodiments, the reaction isperformed in the presence of sodium bicarbonate.

In certain embodiments of the method of Scheme 1, the reaction isperformed in the presence of an organic base. In certain embodiments,the reaction is performed in the presence of an organic base such astriethylamine, tributylamine, diisopropylethylamine,dimethylisopropylamine, N-methylmorpholine, N-methylpyrrolidine,N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine,4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]undec-7-ene,and combinations of any of the foregoing. In certain embodiments, thereaction is performed in the presence of an organic base such astriethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, orcombinations of any of the foregoing.

In another embodiment, a compound of Formula (V), where R¹⁰ istrialkylsilyl or aryldialkylsilyl, may be prepared directly fromcompound (III) by silylation (e.g., using a silyl halide or silylamidereagent) and then acylation of the resulting intermediate with compound(IV) (Scheme 2), where Z is a leaving group such as a halide,p-nitrophenolate, imidazolyl, and the like, and X is a halide, adaptingmethods disclosed by Gallop et al., U.S. Application Publication No.2004/0014940, which is incorporated by reference herein in its entirety.

Suitable solvents for performing this reaction include, for example,dichloromethane, dichloroethane, chloroform, toluene, pyridine, andacetonitrile. Suitable bases for performing this reaction include, forexample, triethylamine, tributylamine, diisopropylethylamine,dimethylisopropylamine, N-methylmorpholine, N-methylpyrrolidine,N-methylpiperidine, pyridine, 2-methylpyridien, 2,6-dimethylpyridine,4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, and1,5-diazabicyclo[4.3.0]undec-7-ene. The reaction can be performed at atemperature from about −78° C. to about 50° C., and in certainembodiments, at a temperature from about −20° C. to about 25° C.

1-Acyloxyalkylcarbamates of Formula (I) can be prepared from compoundsof Formula (V) by treatment with carboxylic acids of the formula R¹COOHin the presence of an organic or inorganic base, or other metal salt.Examples of useful solvents, bases and other reaction conditions aredescribed in Gallop et al., U.S. Application Publication No.2004/0014940. The carboxylic acid protecting group, R¹⁰, can be removedunder mild conditions to provide a compound of Formula (I) where R¹⁰ ishydrogen. Carboxylic acid protecting groups removable via mild acidichydrolysis, fluoride ion-promoted hydrolysis, catalytic hydrogenolysis,transfer hydrogenolysis, or other transition metal-mediated deprotectionreactions. In certain embodiments, R¹⁰ is trimethylsilyl.

Pharmaceutical Compositions

Pharmaceutical compositions provided by the present disclosure comprisea compound of Formula (I) and a pharmaceutically acceptable vehicle. Thepharmaceutical compositions may comprise a therapeutically effectiveamount of compound of Formula (I) and at least one pharmaceuticallyacceptable vehicle. In certain embodiments, the pharmaceuticalcompositions may include more than one compound of Formula (I).Pharmaceutically acceptable vehicles include diluents, adjuvants,excipients, and carriers.

Pharmaceutical compositions may be produced using standard procedures(see, e.g., “Remington's The Science and Practice of Pharmacy,” 21 stedition, Lippincott, Williams & Wilcox, 2005). Pharmaceuticalcompositions may be manufactured by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, and lyophilizing processes. Pharmaceuticalcompositions may be formulated in a conventional manner using one ormore physiologically acceptable carriers, diluents, excipients, orauxiliaries, which facilitate processing of compounds disclosed hereininto preparations, which may be used pharmaceutically. Properformulation may depend, in part, on the route of administration.

Pharmaceutical compositions provided by the present disclosure mayprovide therapeutic or prophylactic levels of an α-amino acid uponadministration to a patient. The promoiety of an α-amino acid prodrugmay be cleaved in vivo either chemically and/or enzymatically to releasethe corresponding α-amino acid. One or more enzymes present in theintestinal lumen, intestinal tissue, blood, liver, brain, or any othersuitable tissue of a mammal may enzymatically cleave the promoiety ofthe administered prodrugs. For example, the promoiety may be cleavedwithin the intestinal lumen and/or after absorption by thegastrointestinal tract (e.g., in intestinal tissue, blood, liver, orother suitable tissue of a mammal). In certain embodiments, the α-aminoacid remains conjugated to the promoiety during transit across theintestinal mucosal barrier to provide protection from presystemicmetabolism. In certain embodiments, the α-amino acid prodrug isessentially not metabolized to release the corresponding α-amino acidwithin enterocytes, but is metabolized to the parent drug within thesystemic circulation. Cleavage of the promoiety of the α-amino acidprodrug after absorption by the gastrointestinal tract may allow theprodrug to be absorbed into the systemic circulation by activetransport, passive diffusion, or by a combination of both active andpassive processes.

Alpha-amino acid prodrugs may remain intact until after passage of theprodrug through a biological barrier, such as the blood-brain-barrier.In certain embodiments, α-amino acid prodrugs provided by the presentdisclosure can be partially cleaved, e.g., one or more, but not all, ofthe promoieties may be cleaved before passage through a biologicalbarrier or prior to being taken up by a cell, tissue, or organ.

Alpha-amino acid prodrugs may remain intact in the systemic circulationand be absorbed by cells of an organ, either passively or by activetransport mechanisms. In certain embodiments, the α-amino acid prodrugsare lipophilic and may passively translocate through cellular membranes.Following cellular uptake, the prodrugs may be cleaved chemically and/orenzymatically to release the corresponding α-amino acids into thecellular cytoplasm, resulting in an increase in the intracellularconcentration of the α-amino acids. In certain embodiments, the prodrugsmay be permeable to intracellular membranes such as the mitochondrialmembrane, and thereby facilitate delivery of the prodrugs, and followingcleavage of the promoiety or promoieties, an α-amino acid, to anintracellular organelle.

In certain embodiments, the pharmaceutical compositions comprise atleast one compound of Formula (I) in an amount effective for thetreatment of a neuropsychiatric or neurodegenerative disorder in apatient. In certain embodiments, the pharmaceutical compositionscomprise at least one compound of Formula (I) in an amount effective forthe treatment of a neuropsychiatric or neurodegenerative disorderassociated with glutamatergic neurotransmission dysfunction. In certainembodiments; the pharmaceutical compositions comprise at least onecompound of Formula (I) in an amount effective for the treatment of aneuropsychiatric or neurodegenerative disorder chosen from a psychoticdisorder such as schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, drug-induced psychoticdisorder, or an illness associated with psychosis including majordepression, bipolar disorder, and post-traumatic stress syndrome; acognitive disorder such as dementia associated with, for example,Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV,Pick's disease, and Creutzfeldt-Jakob disease, amnestic disorders, andage-related cognitive decline; an anxiety disorder such as generalizedanxiety disorder, obsessive compulsive disorder, social phobia, panicattack, mood disorders including depression, seasonal depression,postpartum depression, premenstrual syndrome, and premenstrual dysphoricdisorder; attention disorders including attention deficit hyperactivitydisorder and autism; and movement disorders such as Parkinsonism,akinesias, akathesias, and dyskinesias including tardive dyskinesia,dystonia, spasticity, epilepsy, and Tourette's syndrome.

In certain embodiments, a pharmaceutical composition comprises at leastone compound of Formula (I) in an amount effective for the treatment ofa substance-related disorder or addictive behavior, including, forexample, substance-induced delirium, persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder; or toleranceof, dependence on, or withdrawal from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine,opioids, phencyclidine, sedatives, hypnotics, and anxiolytics.

In certain embodiments, a pharmaceutical composition comprises at leastone compound of Formula (I) in an amount effective for the treatment ofobesity, bulimia nervosa, or a compulsive eating disorder.

In certain embodiments, the pharmaceutical compositions comprise atleast one compound of Formula (I) in an amount effective for thetreatment of a learning disorder, pervasive developmental disorderincluding autistic disorder, attention disorders includingattention-deficit hyperactivity disorder (ADHD), or conduct disorder.

In certain embodiments, the pharmaceutical compositions comprise atleast one compound of Formula (I) in an amount effective for thetreatment of NMDA receptor-related disorders such as autism, depression,benign forgetfulness, childhood learning disorder, or closed headinjury.

In certain embodiments, the pharmaceutical compositions comprise atleast one compound of Formula (I) in an amount effective for thetreatment of urinary incontinence, neuronal damage including oculardamage, retinopathy or macular degeneration of the eye, tinnitus,hearing impairment or loss, brain edema, emesis, or a sleep disorderincluding insomnia and narcolepsy.

In certain embodiments, the pharmaceutical compositions include anadjuvant that facilitates absorption of the at least one compound ofFormula (I) through the gastrointestinal epithelia. Such enhancers can,for example, open the tight-junctions in the gastrointestinal tract ormodify the effect of cellular components, such as p-glycoprotein and thelike. Suitable enhancers include alkali metal salts of salicylic acid,such as sodium salicylate, caprylic or capric acid, such as sodiumcaprylate or sodium caprate, and the like. Suitable enhancers alsoinclude, for example, bile salts, such as sodium deoxycholate. Variousp-glycoprotein modulators are described in Fukazawa et al., U.S. Pat.No. 5,112,817 and Pfister et al., U.S. Pat. No. 5,643,909. Variousabsorption enhancing compounds and materials are described in Burnsideet al., U.S. Pat. No. 5,824,638, and Meezam et al., U.S. ApplicationPublication No. 2006/0046962. Other adjuvants that enhance permeabilityof cellular membranes include resorcinol, surfactants, polyethyleneglycol, and bile acids.

In certain embodiments, the pharmaceutical compositions include anadjuvant that reduces enzymatic degradation of the at least one compoundof Formula (I). Microencapsulation using protenoid microspheres,liposomes, or polysaccharides may also be effective in reducingenzymatic degradation of administered compounds.

The pharmaceutical compositions may also include one or morepharmaceutically acceptable vehicles, including excipients, adjuvants,carriers, diluents, binders, lubricants, disintegrants, colorants,stabilizers, surfactants, fillers, buffers, thickeners, emulsifiers,wetting agents, and the like. Vehicles can be selected to alter theporosity and permeability of a pharmaceutical composition, alterhydration and disintegration properties, control hydration, enhancemanufacturability, etc.

In certain embodiments, the pharmaceutical compositions are formulatedfor oral administration. Pharmaceutical compositions formulated for oraladministration can provide for uptake of a compound of Formula (I)throughout the gastrointestinal tract, or even in a particular region orregions of the gastrointestinal tract. In certain embodiments, thepharmaceutical compositions may be formulated to enhance uptake acompound of Formula (I) from the upper gastrointestinal tract, and incertain embodiments, from the small intestine. Such compositions may beprepared in a manner known in the pharmaceutical arts and may furthercomprise, in addition to a compound of Formula (I), one or morepharmaceutically acceptable vehicles, penmeability enhancers, and/or asecond therapeutic agent.

In certain embodiments, the pharmaceutical compositions further comprisea substance to enhance, modulate and/or control release,bioavailability, therapeutic efficacy, therapeutic potency, stability,etc., of a compound of Formula (I). For example, to enhance therapeuticefficacy a compound of Formula (I) may be co-administered with one ormore active agents to increase the absorption or diffusion of the drugfrom the gastrointestinal tract, or to inhibit degradation of the drugin the systemic circulation. In certain embodiments, the compound ofFormula (I) is co-administered with active agents having pharmacologicaleffects that enhance the therapeutic efficacy of the compound of Formula(I).

Pharmaceutical compositions may take the form of solutions, suspensions,emulsions, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse.

Pharmaceutical compositions comprising a compound of Formula (I) may beformulated for oral administration. Pharmaceutical compositions for oraldelivery may be in the form of tablets, lozenges, aqueous or oilysuspensions, granules, powders, emulsions, capsules, syrups, or elixirs,for example. Orally administered compositions may comprise one or moreoptional agents, for example, sweetening agents such as fructose,aspartame, and saccharin; flavoring agents such as peppermint, oil ofwintergreen, and cherry; coloring agents; and preserving agents, toprovide a pharmaceutically palatable preparation. Moreover, when intablet or pill form, the compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time. Oralcompositions may include standard vehicles such as mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate, etc. Such vehicles may be of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirs,and solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol), oils, alcohols, slightly acidic buffershaving a pH ranging from about pH 4 to about pH 6 (e.g., acetate,citrate, ascorbate at between about 5 mM to about 50 mM), etc.Additionally, flavoring agents, preservatives, coloring agents, bilesalts, acylcarnitines, and the like may be added.

When compounds of Formula (I) are acidic, they may be included in any ofthe above-described formulations as free acids, pharmaceuticallyacceptable salts, solvates, or hydrates. Pharmaceutically acceptablesalts substantially retaining the activity of the free acid forms may beprepared by reaction with bases, and tend to be more soluble in aqueousand other protic solvents than the corresponding free acid forms. Insome embodiments, sodium salts of a compound of Formula (I) are used inthe above-described formulations.

Pharmaceutical compositions provided by the present disclosure may beformulated for parenteral administration including administration byinjection, for example, into a vein (intravenously), an artery(intraarterially), a muscle (intramuscularly), under the skin(subcutaneously or in a depot formulation), to the pericardium, to thecoronary arteries, or used as a solution for delivery to a tissue ororgan, for example, use in a cardiopulmonary bypass machine or to bathetransplant tissues or organs. Injectable compositions may bepharmaceutical compositions for any route of injectable administrationincluding, but not limited to, intravenous, intraarterial,intracoronary, pericardial, perivascular, intramuscular, subcutaneous,intradermal, intraperitoneal, and intraarticular. In certainembodiments, the injectable pharmaceutical compositions arepharmaceutically appropriate compositions for administration directlyinto the heart, pericardium or coronary arteries.

Pharmaceutical compositions provided by the present disclosure suitablefor parenteral administration may comprise one or more compounds ofFormula (I) in combination with one or more pharmaceutically acceptablesterile isotonic aqueous, water-miscible, or non-aqueous vehicles.Pharmaceutical compositions for parenteral use may include substancesthat increase and maintain drug solubility such as complexing agents andsurface acting agents, compounds that make the solution isotonic or nearphysiological pH such as sodium chloride, dextrose, and glycerin,substances that enhance the chemical stability of solutions such asantioxidants, inert gases, chelating agents, and buffers, substancesthat enhance chemical and physical stability, substances that minimizeself-aggregation or interfacial induced aggregation, substances thatminimize protein interaction with interfaces, preservatives includingantimicrobial agents, suspending agents, emulsifying agents, andcombinations of any of the foregoing. Pharmaceutical compositions forparenteral administration may be formulated as solutions, suspensions,emulsions, liposomes, microspheres, nanosystems, and powder to bereconstituted as solutions. Parenteral preparations are described in“Remington, The Science and Practice of Pharmacy,” 21 st edition,Lippincott, Williams & Wilkins, Chapter 41-42, pages 802-849, 2005.

For prolonged delivery, pharmaceutical compositions may be provided asdepot preparations, for administration by implantation, e.g.,subcutaneous, intradermal, or intramuscular injection. Thus, in certainembodiments, the pharmaccutical compositions are formulated withsuitable polymeric or hydrophobic materials, e.g., as an emulsion in apharmaceutically acceptable oil, ion exchange resins, or as a sparinglysoluble derivative, e.g., as a sparingly soluble salt form of a compoundof Formula (I).

Pharmaceutical compositions provided by the present disclosure may beformulated so as to provide immediate, sustained, or delayed release ofa compound of Formula (I) after administration to the patient byemploying procedures known in the art (see, e.g., Allen et al., “Ansel'sPharmaceutical Dosage Forms and Drug Delivery Systems,” 8th ed.,Lippincott, Williams & Wilkins, August 2004). In certain embodiments,pharmaceutical compositions comprising a compound of Formula (I) areformulated for sustained release, and in certain embodiments, for oralsustained release.

Dosage Forms

Pharmaceutical compositions provided by the present disclosure may beformulated in a unit dosage form. Unit dosage form refers to aphysically discrete unit suitable as a unitary dose for patientsundergoing treatment, with each unit containing a predetermined quantityof at least one compound of Formula (I) calculated to produce theintended therapeutic effect. A unit dosage form may be for a singledaily dose, once or twice per day, or one of multiple daily doses, e.g.,2, 3, or 4 times per day. When multiple daily doses are used, the unitdosage may be the same or different for each dose. One or more dosageforms may comprise a dose, which can be administered to a patient at asingle point in time or during a time interval.

Pharmaceutical compositions provided by the present disclosure may beused in dosage forms that provide immediate release and/or controlledrelease of the at least one compound of Formula (I). The appropriatetype of dosage form will depend on the disease, disorder, or conditionbeing treated, and on the method of administration. For example, for thetreatment of an acute neuropsychiatric or neurodegenerative disorder animmediate release pharmaceutical composition or dosage form administeredparenterally may be used. For treatment of chronic neuropsychiatric orneurodegenerative disorders, a controlled release pharmaceuticalcomposition and/or dosage form administered orally may be used.

In certain embodiments, the dosage forms are adapted to be administeredto a patient no more than twice per day, and in certain embodiments,only once per day. Dosing may be provided alone or in combination withother drugs, and may continue as long as required for effectivetreatment of the neuropsychiatric or neurodegenerative disorder.

Pharmaceutical compositions comprising the at least one compound ofFormula (I) may be formulated for immediate release for parenteraladministration, oral administration, or by any other appropriate routeof administration.

Controlled drug delivery systems may be designed to deliver a drug insuch a way that the drug level is maintained within the therapeuticwindows and effective and safe blood levels are maintained for a periodas long as the system continues to deliver the drug at a particularrate. Controlled drug delivery may produce substantially constant bloodlevels of a drug as compared to fluctuations observed with immediaterelease dosage forms. For some drugs, maintaining a constant bloodstreamand tissue concentration throughout the course of therapy is the mostdesirable mode of treatment. Immediate release of these drugs may causeblood levels to peak above the level required to elicit the desiredresponse, which wastes the drug and may cause or exacerbate toxic sideeffects. Controlled drug delivery can result in optimum therapy, and mayreduce the frequency of dosing as well as reduce the severity of sideeffects. Examples of controlled release dosage forms include dissolutioncontrolled systems, diffusion controlled systems, ion exchange resins,osmotically controlled systems, erodable matrix systems, pH independentformulations, gastric retention systems, and the like.

In certain embodiments, the oral dosage forms of the present disclosuremay be controlled release dosage forms. Controlled delivery technologiesmay improve the absorption of the drug in a particular region or regionsof the gastrointestinal tract.

The appropriate oral dosage form for a particular pharmaceuticalcomposition may depend, at least in part, on the gastrointestinalabsorption properties of the compound of Formula (I), the stability ofthe compound of Formula (I) in the gastrointestinal tract, thepharmacokinetics of the compound of Formula (I), and the intendedtherapeutic profile. An appropriate controlled release oral dosage formmay be selected for particular compounds of Formula (I). For example,gastric retention oral dosage forms may be appropriate for compoundsabsorbed primarily from the upper gastrointestinal tract, and sustainedrelease oral dosage forms may be appropriate for compounds absorbedprimarily from the lower gastrointestinal tract.

Certain compounds are absorbed primarily from the small intestine. Ingeneral, compounds traverse the length of the small intestine in about 3to 5 hours. For compounds that are not easily absorbed by the smallintestine or that do not dissolve readily, the window for active agentabsorption in the small intestine may be too short to provide thedesired therapeutic effect.

Gastric retention dosage forms, i.e., dosage forms that are designed tobe retained in the stomach for a prolonged period of time, may increasethe bioavailability of drugs that are most readily absorbed by the uppergastrointestinal tract. The residence time of a conventional dosage formin the stomach ranges from 1 to 3 hours. After transiting the stomach,there is approximately a 3 to 5 hour window of bioavailability beforethe dosage form reaches the colon. However, if the dosage form isretained in the stomach, the drug may be released before it reaches thesmall intestine and will enter the intestine in solution in a state inwhich it can be more readily absorbed. Another use of gastric retentiondosage forms is to improve the bioavailability of drugs that areunstable to the basic conditions of the intestine (see, e.g., Hwang etal., Critical Reviews in Therapeutic Drug Carrier Systems, 1998, 15,243-284).

To enhance drug absorption from the upper gastrointestinal tract,several gastric retention dosage forms have been developed. Examplesinclude, hydrogels (see, e.g., Gutierrez-Rocca et al., U.S. ApplicationPublication No. 2003/0008007), buoyant matrices (see, e.g., Lohray etal., Application Publication No. 2006/0013876), polymer sheets (see,e.g., Mohammad, Application Publication No. 2005/0249798), microcellularfoams (see, e.g., Clarke et al., Application Publication No.2005/0202090), and swellable dosage forms (see, e.g., Edgren et al.,U.S. Application Publication No. 2005/0019409; Edgren et al., U.S. Pat.No. 6,797,283; Jacob et al., U.S. Application Publication No.2006/0045865; Ayres, U.S. Application Publication No. 2004/0219186;Gusler et al., U.S. Pat. No. 6,723,340; Flashner-Barak et al., U.S. Pat.No. 6,476,006; Wong et al., U.S. Pat. Nos. 6,120,803 and 6,548,083;Shell et al., U.S. Pat. No. 6,635,280; and Conte et al., U.S. Pat. No.5,780,057).

In a swelling and expanding system, dosage forms that swell and changedensity in relation to the surrounding gastric content can be retainedin the stomach for longer than a conventional dosage form. A dosage formcan absorb water and swell to form a gelatinous outside surface andfloat on the surface of gastric content surface while maintainingintegrity before releasing a drug. Fatty materials may be added toimpede wetting and enhance flotation, for example, when hydration andswelling alone are insufficient. Materials that release gases may alsobe incorporated to reduce the density of the gastric retention dosageforms. Swelling also can significantly increase the size of a dosageform and thereby impede discharge of the non-disintegrated swollen soliddosage form through the pylorus into the small intestine. Swellabledosage forms may be formed by encapsulating a core containing drug and aswelling agent, or by combining a drug, swelling agent, and one or moreerodible polymers.

Gastric retention dosage forms may also be in the form of a folded thinsheet containing a drug and water-insoluble diffusible polymer thatopens in the stomach to its original size and shape, which issufficiently large to prevent or inhibit passage of the expanded dosagefrom through the pyloric sphincter.

Floating and buoyancy gastric retention dosage forms may be designed totrap gases within sealed encapsulated cores that can float on thegastric contents, and thereby be retained in the stomach for a longertime, e.g., from about 9 to about 12 hours. Due to the buoyancy effect,these systems can provide a protective layer preventing the reflux ofgastric content into the esophageal region and can also be used forcontrolled release devices. A floating system may, for example, containhollow cores containing drug coated with a protective membrane. Thetrapped air in the cores floats the dosage from on the gastric contentuntil the soluble ingredients are released and the system collapses. Inother floating systems, cores comprise drug and chemical substancescapable of generating gases when activated. For example, coated cores,comprising carbonate and/or bicarbonate can generate carbon dioxide froma reaction with hydrochloric acid in the stomach or incorporated organicacid in the system. The gas generated by the reaction is retained tofloat the dosage form. The inflated dosage form later collapses andclears form the stomach when the generated gas permeates slowly throughthe protective coating.

Bioadhesive polymers may also be used to provide a vehicle forcontrolled delivery of drugs to a number of mucosal surfaces in additionto the gastric mucosa (see, e.g., Mathiowitz et al., U.S. Pat. No.6,235,313; and Illum et al., U.S. Pat. No. 6,207,197). A bioadhesivesystem can be designed by incorporation of a drug and other excipientswithin a bioadhesive polymer. On ingestion, the polymer hydrates andadheres to the mucus membrane of the gastrointestinal tract. Bioadhesivepolymers can be selected that adhere to a desired region or regions ofthe gastrointestinal tract. Bioadhesive polymers can be selected tooptimized delivery to targeted regions of the gastrointestinal tractincluding the stomach and small intestine. The mechanism of the adhesionis thought to be through the formation of electrostatic and hydrogenbonding at the polymer-mucus boundary. Jacob et al., U.S. ApplicationPublication Nos. 2006/0045865 and 2005/0064027, disclose bioadhesivedelivery systems which are useful for drug delivery to both the upperand lower gastrointestinal tract.

Ion exchange resins have also been shown to prolong gastric retention,potentially by adhesion.

Gastric retention oral dosage forms may be appropriately used fordelivery of drugs that are absorbed mainly from the uppergastrointestinal tract. For example, certain compounds of Formula (I)may exhibit limited colonic absorption, and be absorbed primarily fromthe upper gastrointestinal tract. Thus, dosage forms that release thecompound of Formula (I) in the upper gastrointestinal tract and/orretard transit of the dosage form through the upper gastrointestinaltract will tend to enhance the oral bioavailability of the compound ofFormula (I). Other forms of α-amino acids disclosed herein may beappropriately used with gastric retention dosage forms.

Polymer matrices have also been used to achieve controlled release ofdrugs over a prolonged period of time. Such sustained or controlledrelease may be achieved by limiting the rate by which the surroundinggastric fluid can diffuse through the matrix and reach the drug,dissolve the drug and diffuse out again with the dissolved drug, or byusing a matrix that slowly erodes, continuously exposing fresh drug tothe surrounding fluid. Disclosures of polymer matrices that function bythese methods are found, for example, in Skinner, U.S. Pat. Nos.6,210,710 and 6,217,903; Rencher et al., U.S. Pat. No. 5,451,409; Kim,U.S. Pat. No. 5,945,125; Kim, PCT International Publication No. WO96/26718; Ayer et al., U.S. Pat. No. 4,915,952; Akhtar et al., U.S. Pat.No. 5,328,942; Fassihi et al., U.S. Pat. No. 5,783,212; Wong et al.,U.S. Pat. No. 6,120,803; and Pillay et al., U.S. Pat. No. 6,090,411.

Other drug delivery devices that remain in the stomach for extendedperiods of time include, for example, hydrogel reservoirs comprisingparticles (Edgren et al., U.S. Pat. No. 4,871,548); swellablehydroxypropylmethylcellulose polymers (Edgren et al., U.S. Pat. No.4,871,548); planar biocrodible polymers (Caldwell et al., U.S. Pat. No.4,767,627); plurality of compressible retention arms (Curatolo et al.,U.S. Pat. No. 5,443,843); hydrophilic water-swellable, cross-linkedpolymer particles (Shell, U.S. Pat. No. 5,007,790); andalbumin-cross-linked polyvinylpyrrolidone hydrogels (Park et al., J.Controlled Release 1992, 19, 131-134).

In certain embodiments, pharmaceutical compositions of the presentdisclosure are formulated into a number of different dosage forms, whichmay be adapted to provide sustained release of the compound of Formula(I) upon oral administration. Sustained release oral dosage formsinclude any oral dosage form that maintains therapeutic concentrationsof a drug in a biological fluid such as the plasma, blood, cerebrospinalfluid, or in a tissue or organ for a prolonged time period. Sustainedrelease oral dosage forms may be used to release drugs over a prolongedtime period and are useful when it is desired that a drug or drug formbe delivered to the lower gastrointestinal tract. Sustained release oraldosage forms include diffusion-controlled systems such as reservoirdevices and matrix devices, dissolution-controlled systems, osmoticsystems, and erosion-controlled systems. Sustained release oral dosageforms and methods of preparing the same are well known in the art (see,for example, “Remington's Pharmaceutical Sciences,” Lippincott, Williams& Wilkins, 21st edition, 2005, Chapters 46 and 47; Langer, Science 1990,249, 1527-1533; and Rosoff, “Controlled Release of Drugs,” 1989, Chapter2).

In diffusion-controlled systems, a water-insoluble polymer controls theflow of fluid and the subsequent egress of dissolved drug from thedosage form. Both diffusional and dissolution processes are involved inrelease of drug from the dosage form. In reservoir devices, a corecomprising a drug is coated with the polymer, and in matrix systems, thedrug is dispersed throughout the matrix. Cellulose polymers such asethylcellulose and cellulose acetate may be used in reservoir devices.Examples of materials useful in matrix systems include, but are notlimited to, methacrylates, acrylates, polyethylene, acrylic acidcopolymers, polyvinylchloride, high molecular weight polyvinylalcohols,cellulose derivates, and fatty compounds such as fatty acids,glycerides, and carnauba wax.

In dissolution-controlled systems, the rate of dissolution of the drugis controlled by slowly soluble polymers or by microencapsulation. Oncethe coating is dissolved, the drug becomes available for dissolution. Byvarying the thickness and/or the composition of the coating or coatings,the rate of drug release may be controlled. In somedissolution-controlled systems, a fraction of the total dose maycomprise an immediate-release component. Dissolution-controlled systemsinclude encapsulated/reservoir dissolution systems and matrixdissolution systems. Encapsulated dissolution systems may be prepared bycoating particles or granules of drug with slowly soluble polymers ofdifferent thickness or by microencapsulation. Examples of coatingmaterials useful in dissolution-controlled systems include, but are notlimited to, gelatin, carnauba wax, shellac, cellulose acetate phthalate,and cellulose acetate butyrate. Matrix dissolution devices may beprepared, for example, by compressing a drug with a slowly solublepolymer carrier into a tablet form.

The rate of release of drug from osmotic pump systems is determined bythe inflow of fluid across a semipermeable membrane into a reservoir,which contains an osmotic agent. The drug may be mixed with the agent ormay be located in a reservoir. The dosage form contains one or moresmall orifices from which dissolved drug is pumped at a rate determinedby the rate of entrance of water due to osmotic pressure. As osmoticpressure within the dosage form increases, the drug is released throughthe orifice(s). The rate of release is constant and may be controlledwithin tight limits yielding relatively constant plasma and/or bloodconcentrations of the drug. Osmotic pump systems may provide a constantrelease of drug independent of the environment of the gastrointestinaltract. The rate of drug release may be modified by altering the osmoticagent and the sizes of the one or more orifices.

The release of drug from erosion-controlled systems is determined by theerosion rate of a carrier matrix. Drug is dispersed throughout thepolymer and the rate of drug release depends on the erosion rate of thepolymer. The drug-containing polymer may degrade from the bulk and/orfrom the surface of the dosage form.

Sustained release oral dosage forms may be in any appropriate form fororal administration, such as, for example, in the form of tablets,pills, or granules. Granules may be filled into capsules, compressedinto tablets, or included in a liquid suspension. Sustained release oraldosage forms may additionally include an exterior coating to provide,for example, acid protection, ease of swallowing, flavor,identification, etc.

In certain embodiments, sustained release oral dosage forms comprise atherapeutically effective amount of a compound of Formula (I) and apharmaceutically acceptable vehicle. In certain embodiments, sustainedrelease oral dosage forms comprise less than a therapeutically effectiveamount of a compound of Formula (I) and a pharmaceutically effectivevehicle. Multiple sustained release oral dosage forms, each dosage formcomprising less than a therapeutically effective amount of a compound ofFormula (I), may be administered at a single time or over a period oftime to provide a therapeutically effective dose or regimen for treatinga neuropsychiatric or neurodegenerative disorder.

Sustained release oral dosage forms provided by the present disclosurecan release the compound of Formula (I) from the dosage form tofacilitate the ability of the compound of Formula (I) to be absorbedfrom an appropriate region of the gastrointestinal tract, for example,in the small intestine, or in the colon. In certain embodiments, thesustained release oral dosage form releases the compound of Formula (I)from the dosage form over a period of at least about 4 hours, forexample, over at least about 8 hours, at least about 12 hours, at leastabout 16 hours, at least about 20 hours, and in certain embodiments, atleast about 24 hours. In certain embodiments, a sustained release oraldosage form releases a compound of Formula (I) in a delivery patternranging from about 0 wt % to about 20 wt % in from about 0 to about 4hours; from about 20 wt % to about 50 wt % in from about 0 to about 8hours; from about 55 wt % to about 85 wt % in from about 0 to about 14hours; and about 80 wt % to about 100 wt % in from about 0 to about 24hours. In certain embodiments, a sustained release oral dosage formreleases a compound of Formula (I) in a delivery pattern ranging fromabout 0 wt % to about 20 wt % in from about 0 to about 4 hours; fromabout 20 wt % to about 50 wt % in from about 0 to about 8 hours; fromabout 55 wt % to about 85 wt % in about from 0 to about 14 hours; andfrom about 80 wt % to about 100 wt % in from about 0 to about 20 hours.In certain embodiments, a sustained release oral dosage form releases acompound of Formula (I) from the dosage form in a delivery pattern offrom about 0 wt % to about 20 wt % in from about 0 to about 2 hours;from about 20 wt % to about 50 wt % in from about 0 to about 4 hours;from about 55 wt % to about 85 wt % in from about 0 to about 7 hours;and from about 80 wt % to about 100 wt % in from about 0 to about 8hours.

Sustained release oral dosage forms comprising a compound of Formula (I)may provide a concentration of the corresponding α-amino acid in theplasma, blood, or tissue of a patient over time, following oraladministration to the patient. The concentration profile of an α-aminoacid can exhibit an AUC that is proportional to the dose of thecorresponding compound of Formula (I).

Regardless of the specific type of controlled release oral dosage formused, a compound of Formula (I) may be released from an orallyadministered dosage form over a sufficient period of time to provideprolonged therapeutic concentrations of a compound of Formula (I) in theplasma and/or blood of a patient. Following oral administration, adosage form comprising a compound of Formula (I) may provide atherapeutically effective concentration of the corresponding an α-aminoacid in the plasma and/or blood of a patient for a continuous timeperiod for at least about 4 hours, for example, for at least about 8hours, for at least about 12 hours, for at least about 16 hours, and incertain embodiments, for at least about 20 hours, following oraladministration of the dosage form to the patient. The continuous timeperiods during which a therapeutically effective concentration of anα-amino acid is maintained may be the same or different. The continuousperiod of time during which a therapeutically effective plasmaconcentration of an α-amino acid is maintained may begin shortly afteroral administration or after a time interval.

In certain embodiments, an oral dosage for treating a disease, disorder,or condition in a patient comprises a compound of Formula (I) whereinthe oral dosage form is adapted to provide, after a singleadministration of the oral dosage form to the patient, a therapeuticallyeffective concentration of the corresponding α-amino acid in the plasmaof the patient for a first continuous time period chosen from at leastabout 4 hours, for example, at least about 8 hours, at least about 12hours, and at least about 16 hours, and at least about 20 hours.

Regardless of the specific type of sustained release oral dosage formused, compounds may be released from the dosage form over a period of atleast about 4 hours, for example, over a period of at least about 8hours, or over a period of at least about 12 hours. Further, in certainembodiments, a dosage form can release from about 0 to about 30% of theprodrug in from about 0 to about 2 hours, from about 20 to about 50% ofthe prodrug in from about 2 to about 12 hours, from about 50 to about85% of the prodrug in from about 3 to about 20 hours and greater thanabout 75% of the prodrug in from about 5 to about 18 hours. In certainembodiments, the sustained release oral dosage form provides aconcentration of α-amino acid in the blood plasma of a patient overtime, which curve has an AUC proportional to the dose of the prodrug ofα-amino acid administered, and a maximum concentration C_(max). Incertain embodiments, the C_(max) is less than about 75%, and in certainembodiments, is less than about 60%, of the C_(max) obtained fromadministering an equivalent dose of the compound from an immediaterelease oral dosage form, and the AUC is substantially the same as theAUC obtained from administering an equivalent dose of the prodrug froman immediate release oral dosage form.

In certain embodiments, a dosage form is administered once or twice perday, and in certain embodiments, once per day.

Uses of Compounds, Compositions, and Dosage Forms

Compounds of Formula (I) and pharmaceutical compositions comprisingcompounds of Formula (I) have utility in treating neurological andpsychiatric disorders associated with glutamatergic neurotransmissiondysfunction, including one or more of the following conditions anddiseases: schizophrenia or psychosis including schizophrenia (e.g.,paranoid, disorganized, catatonic, or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (phencyclidine, ketamine and other dissociativeanesthetics, amphetamine and other psychostimulants and cocaine)psychosispsychotic disorder, psychosis associated with affectivedisorders, brief reactive psychosis, schizoaffective psychosis,“schizophrenia-spectrum” disorders such as schizoid and schizotypalpersonality disorders, illness associated with psychosis (such as majordepression, manic depressive (bipolar) disorder, Alzheimer's disease,and post-traumatic stress syndrome), including the positive, negative,and cognitive symptoms of schizophrenia and other psychoses; cognitivedisorders including dementia (associated with Alzheimer's disease,ischemia, multi-infarct dementia, trauma, vascular problems and stroke,HTV disease, Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jakob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium; amnestic disorders and agerelated cognitive decline; anxiety disorders including acute stressdisorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder, and anxietydue to a general medical condition; substance-related disorders andaddictive behaviors (including substance-induced delirium, persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder; tolerance of, dependence on, or withdrawal from substancesincluding alcohol, amphetamines, cannabis, cocaine, hallucinogens,inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics, andanxiolytics); obesity, bulimia nervosa, and compulsive eating disorders;bipolar disorders; mood disorders including depressive disorders;depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders; learning disorders,pervasive developmental disorder including autistic disorder, attentiondisorders including attention-deficit hyperactivity disorder (ADHD) andconduct disorder; NMDA receptor-related disorders such as autism,depression, benign forgetfulness, childhood learning disorders andclosed head injury; movement disorders, including akinesias andakinetic-rigid syndromes (including Parkinson's disease, drug-inducedParkinsonism, postencephalitic Parkinsonism, progressive supranuclearpalsy, multiple system atrophy, corticobasal degeneration,Parkinsonism-ALS dementia complex and basal ganglia calcification),medication-induced Parkinsonism (such as neuroleptic-inducedParkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia, and medication-induced postural tremor), Tourette'ssyndrome, epilepsy, muscular spasms, and disorders associated withmuscular spasticity or weakness including tremors; dyskinesias(including tremor such as rest tremor, postural tremor, and intentiontremor), chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea, and hemiballism), myoclonus (including generalized myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics), and dystonia (including generalized dystonia such asiodiopathic dystonia, drug-induced dystonia, symptomatic dystonia andparoxymal dystonia, and focal dystonia such as blepharospasm,oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis,axial dystonia, dystonic writer's cramp, and hemiplegic dystonia);urinary incontinence; neuronal damage including ocular damage,retinopathy or macular degeneration of the eye, tinnitus, hearingimpairment or loss, and brain edema; emesis; and sleep disordersincluding insomnia and narcolepsy.

In certain embodiments, the treatable disorders are chosen from at leastone of schizophrenia; bipolar disorder; depression including unipolardepression, seasonal depression and post-partum depression, premenstrualsyndrome (PMS) and premenstrual dysphoric disorder (PDD); learningdisorders, pervasive developmental disorder including autistic disorder;attention disorders including attention-deficit/hyperactivity disorder;autism; tic disorders including Tourette's syndrome; anxiety disordersincluding phobia and post-traumatic stress disorder; cognitive disordersassociated with dementia, AIDS dementia, Alzheimer's disease,Parkinson's disease, and Huntington's disease; spasticity; myoclonus;muscle spasm; and tinnitus and hearing impairment and loss.

For example, the use of NMDA receptor agonists has been shown effectivein treating the positive and cognitive or negative symptoms ofschizophrenia (Tuomien et al., Schizophrenia Research 2005, 72, 225-234;Tsai et al., Biol. Psychiatry 2006, 59, 230-234; Lane et al., Arch. Gen.Psychiatry 2005, 62, 1196-1204; Tsai et al., Biol. Psychiatry 2004, 55,452-456; van Berckel et al., Biol. Psychiatry 1996, 40, 1298-1300;Javitt, Curr Opin Investig Drugs 2002, 3(7), 1067-72; Millan,Psychopharmacology (Berl.) 2005, 179(1), 30-53; Javitt, Curr PsychiatryRep 2001, 3(5), 413-417; Lane et al., Arch. Gen. Psychiatry 2005, 62,1196-1204; and Bennett and Gronier, Eur J Pharmacology 2005, 527,52-59), enhancing memory deficits (Andersen et al.,Neuropsychopharmacology 2004, 29, 1080-1090), relieving anxiety(Richardson et al., Learn. Mem. 2004, 11, 510-516), reversing effects ofalcohol (Rabe and Tabakoff, Molecular Pharmacology 1990, 38, 752-757),and treating ataxia (Ogawa, Cerebellum 2004, 3(2), 107-11; Ogawa et al.,J Neur Sci 2003, 210, 53-56).

In certain embodiments, the present disclosure provides methods fortreating cognitive disorders in a patient comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of Formula (I) or pharmaceutical composition thereof.Examples of cognitive disorders include dementia, delirium, amnesticdisorders, and age-related cognitive decline. The text revision of thefourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR, American Psychiatric Association, Washington D.C.,2000) provides a diagnostic tool that includes cognitive disordersincluding dementia, delirium, amnestic disorders and age-relatedcognitive decline. As used herein, the term “cognitive disorders”includes treatment of those mental disorders as described in DSM-IV-TR.The skilled artisan will recognize that there are alternativenomenclatures and classification systems for mental disorders, and thatthese systems evolve with medical and scientific progress. Thus, theterm “cognitive disorders” is intended to include like disorders thatare described in other diagnostic sources as well.

In certain embodiments, the present disclosure provides methods fortreating anxiety disorders in a patient comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of Formula (I) or pharmaceutical composition thereof.Examples of anxiety disorders are generalized anxiety disorder,obsessive-compulsive disorder, and panic attack. The text revision ofthe fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR, American Psychiatric Association, Washington D.C.,2000) provides a diagnostic tool that includes anxiety disorders,generalized anxiety disorder, obsessive-compulsive disorder and panicattack. As used herein, the term “anxiety disorders” includes treatmentof those mental disorders as described in DSM-IV-TR. The skilled artisanwill recognize that there are alternative nomenclatures andclassification systems for mental disorders, and that these systemsevolve with medical and scientific progress. Thus, the term “anxietydisorders” is intended to include like disorders that are described inother diagnostic sources as well.

In certain embodiments, the present disclosure provides methods fortreating schizophrenia or psychosis in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I) or pharmaceuticalcomposition thereof. Examples of schizophrenia or psychosis pathologiesare paranoid, disorganized, catatonic or undifferentiated schizophrenia,and substance-induced psychotic disorder. The text revision of thefourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR, American Psychiatric Association, Washington D.C.,2000) provides a diagnostic tool that includes paranoid, disorganized,catatonic, or undifferentiated schizophrenia, and substance-inducedpsychotic disorder. As used herein, the term “schizophrenia orpsychosis” includes treatment of those mental disorders as described inDSM-IV-TR. The skilled artisan will recognize that there are alternativenomenclatures and classification systems for mental disorders, and thatthese systems evolve with medical and scientific progress. Thus, theterm “schizophrenia or psychosis” is intended to include like disordersthat are described in other diagnostic sources as well.

In certain embodiments, the present disclosure provides methods fortreating substance-related disorders and addictive behaviors in apatient comprising administering to a patient in need of such treatmenta therapeutically effective amount of a compound of Formula (I) orpharmaceutical composition thereof. Examples of substance-relateddisorders and addictive behaviors include persisting dementia,persisting amnestic disorder, psychotic disorder or anxiety disorderinduced by substance abuse; and tolerance of, dependence on orwithdrawal from substances of abuse. The text revision of the fourthedition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV-TR, American Psychiatric Association, Washington D.C., 2000)provides a diagnostic tool that includes persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder induced bysubstance abuse, and tolerance of, dependence on or withdrawal fromsubstances of abuse. As used herein, the term “substance-relateddisorders and addictive behaviors” includes treatment of those mentaldisorders as described in DSM-IV-TR. The skilled artisan will recognizethat there are alternative nomenclatures and classification systems formental disorders, and that these systems evolve with medical andscientific progress. Thus, the term “substance-related disorders andaddictive behaviors” is intended to include like disorders that aredescribed in other diagnostic sources as well.

In certain embodiments, the present disclosure provides methods fortreating pain in a patient comprising administering to a patient in needof such treatment a therapeutically effective amount of a compound ofFormula (I) or a pharmaceutical composition thereof. Examples of paininclude bone and joint pain such as osteoarthritis, repetitive motionpain, dental pain, cancer pain, myofascial pain such as muscular injuryand fibromyalgia, perioperative pain such as general surgery andgynecological, chronic pain, and neuropathic pain.

In certain embodiments, the present disclosure provides methods fortreating obesity and eating disorders associated with excessive foodintake and complications associated therewith in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I) or pharmaceuticalcomposition thereof. Obesity is included in the tenth edition of theInternational Classification of Diseases and Related Health Problems(ICD-IO) (1992 World Health Organization) as a general medicalcondition. The text revision of the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR, American PsychiatricAssociation, Washington D.C., 2000) provides a diagnostic tool thatincludes obesity in the presence of psychological factors affectingmedical condition. As used herein, the term “obesity or eating disordersassociated with excessive food intake” includes treatment of thosemedical conditions and disorders described in ICD-10 and DSM-IV-TR. Theskilled artisan will recognize that there are alternative nomenclaturesand classification systems for general medical conditions, and thatthese systems evolve with medical and scientific progress. Thus, theterm “obesity or eating disorders associated with excessive food intake”is intended to include similar conditions and disorders that aredescribed in other diagnostic sources as well.

In certain embodiments, methods provided by the present disclosure fortreating neuropsychiatric and neurodegenerative disorders in a patientcomprise administering to a patient in need of such treatment atherapeutically effective amount of a compound of Formula (I) or apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula (I). In certain embodiments, methods of thepresent disclosure comprise administering to a patient a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) for treating neuropsychiatric and/or neurodegenerativedisorder chosen from a psychotic disorder such as schizophrenia,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, drug-induced psychotic disorder, or an illness associated withpsychosis including major depression, bipolar disorder, andpost-traumatic stress syndrome; a cognitive disorder such as dementiaassociated with, for example, Alzheimer's disease, Parkinson's disease,Huntington's disease, HIV, Pick's disease, and Creutzfeldt-Jakobdisease, amnestic disorders, and age-related cognitive decline; ananxiety disorder such as generalized anxiety disorder, obsessivecompulsive disorder, social phobia, panic attack, mood disordersincluding depression, seasonal depression, postpartum depression,premenstrual syndrome, and premenstrual dysphoric disorder, attentiondisorders including attention deficit hyperactivity disorder, andautism; or a movement disorder such as Parkinsonism, akinesias,akathesias, and dyskinesias including tardive dyskinesia, dystonia,spasticity, epilepsy, and Tourette's syndrome.

In certain embodiments, the present disclosure provides methods fortreating a dyskinesia in a patient comprising administering to a patientin need of such treatment a therapeutically effective amount of acompound of Formula (I) or a pharmaceutical composition thereof.Examples of dyskinesia include (including tremor such as rest tremor,postural tremor, and intention tremor), chorea (such as Sydenham'schorea, Huntington's disease, benign hereditary chorea,neuroacanthocytosis, symptomatic chorea, drug-induced chorea, andhemiballism), myoclonus (including generalized myoclonus and focalmyoclonus), tics (including simple tics, complex tics and symptomatictics), and dystonia (including generalized dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp, and hemiplegic dystonia).

In certain embodiments, the present disclosure provides methods fortreating urinary incontinence in a patient comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of Formula (I) or a pharmaceutical composition thereof.

In certain embodiments, the present disclosure provides methods fortreating ncuronal damage in a patient comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of Formula (I) or a pharmaceutical composition thereof.Examples of neuronal damage include ocular damage, retinopathy, maculardegeneration of the eye, tinnitus, hearing impairment or loss, and brainedema.

In certain embodiments, the present disclosure provides methods fortreating emesis in a patient comprising administering to a patient inneed of such treatment a therapeutically effective amount of a compoundof Formula (I) or a pharmaceutical composition thereof.

In certain embodiments, the present disclosure provides methods fortreating sleep disorders in a patient comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of Formula (I) or a pharmaceutical composition thereof. Sleepdisorders are included in the tenth edition of the InternationalClassification of Diseases and Related Health Problems (ICD-IO) (1992World Health Organization) as a general medical condition. The textrevision of the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-IV-TR, American Psychiatric Association,Washington D.C., 2000) provides a diagnostic tool that includes sleepdisorder in the presence of psychological factors affecting medicalcondition and medical disorders. Examples of sleep disorders includeprimary insomnia, primary hypersomnia, narcolepsy, breathing-relatedsleep disorder, circadian rhythm sleep disorder, and other dyssomniasand parasomnias. The skilled artisan will recognize that there arealternative nomenclatures and classification systems for general medicalconditions, and that these systems evolve with medical and scientificprogress. Thus, the term “sleep disorder” is intended to include likeconditions and disorders that are described in other diagnostic sourcesas well.

In certain embodiments, the present disclosure provides methods fortreating a disease in a patient comprising administering to a patient inneed of such treatment a therapeutically effective amount of a compoundof Formula (I) or a pharmaceutical composition thereof, wherein thedisease is chosen from post-partum depression, premenstrual syndrome,premenstrual dysphoric disorder, a learning disorder, autistic disorder,attention-deficit hyperactivity disorder, Tourette's syndrome, phobia,post-traumatic stress disorder, dementia, AIDS dementia, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, spasticity,myoclonus, muscle spasm, tinnitus, hearing impairment, hearing loss,depression, anxiety, bipolar disorder, a substance abuse disorder, andurinary incontinence.

In certain embodiments, the present disclosure provides methods fortreating a disease in a patient comprising administering to a patient inneed of such treatment a therapeutically effective amount of a compoundof Formula (I) or a pharmaceutical composition thereof, wherein thedisease is schizophrenia.

The efficacy of the pharmaceutical compositions, dosage forms, andmethods provided by the present disclosure for treating a diseasedisclosed herein may be determined by methods known to those skilled inthe art. For example, one or more symptoms of a disease being treatedcan be measured before and after treatment of the patient. A reductionin such symptom(s) indicates that the patient's condition has improved.Improvement in the symptoms of the disease may be assessed usingmeasures generally recognized in the art. The efficacy of pharmaceuticalcompositions, dosage forms and methods provided by the presentdisclosure may also be evaluated using animal models using methodsrecognized in the art.

For example, the efficacy of compounds of Formula (I) and pharmaceuticalcompositions of any of the foregoing for treating schizophrenia may bedetermined by methods known to those skilled in the art. For example,negative, positive, and/or cognitive symptom(s) of schizophrenia may bemeasured before, during, and/or after treating the patient. Reduction insuch symptom(s) indicates that a patient's condition has improved.Improvement in the symptoms of schizophrenia may be assessed using, forexample, the Scale for Assessment of Negative Symptoms (SANS), Positiveand Negative Symptoms Scale (PANSS) (see, e.g., Andreasen, 1983, Scalesfor the Assessment of Negative Symptoms (SANS), Iowa City, Iowa; and Kayet al., Schizophrenia Bulletin 1987, 13, 261-276), and using CognitiveDeficits tests such as the Wisconsin Card Sorting Test (WCST) and othermeasures of cognitive function (see, e.g., Keshavan et al., SchizophrRes 2004, 70(2-3), 187-194; Rush, Handbook of Psychiatric Measures,American Psychiatric Publishing, 2000; Sajatovic and Ramirez, RatingScales in Mental Health, 2nd ed, Lexi-Comp, 2003, Keefe, et al.,Schizophr Res. 2004, 68(2-3), 283-97; and Keefe et al.,Neuropsychopharmacology, 19 Apr. 2006).

The efficacy of Formula (I) and pharmaceutical compositions of any ofthe foregoing may be evaluated using animal models of schizophrenicdisorders (see e.g., Geyer and Moghaddam, in “Neuropsychopharmacology,”Davis et al., Ed., Chapter 50, 689-701, American College ofNeuropsychopharmacology, 2002). For example, conditioned avoidanceresponse behavior (CAR) and catalepsy tests in rats are shown to beuseful in predicting antipsychotic activity and EPS effect liability,respectively (Wadenberg et al., Neuropsychopharmacology, 2001, 25,633-641). Other and animal models of schizophrenia are disclosed, forexample, in Sams-Dodd, Rev Neurosci 1999, 10(1), 59-90; Siuciak et al.,Neuropharmacology 2007, 52, 279-290; Levkovitz et al., Brain Res 2007,1154, 154-162; and Wang et al., Neuropharmacology 2007, 52, 1179-1187.Another useful animal model of schizophrenia is the PCP-inducedhyperactivity model as described by Williams et al., ProgressNeuro-Pharmacology & Biological Psychiatry 2006, 30, 239-243.

The efficacy of administering a compound of Formula (I) for treatingParkinson's disease may be assessed using animal and human models ofParkinson's disease and clinical studies. Animal and human models ofParkinson's disease are known (see, e.g., O'Neil et al., CNS Drug Rev.2005, 11(1), 77-96; Faulkner et al., Ann. Pharmacother. 2003, 37(2),282-6; Olson et al., Am. J. Med. 1997, 102(1), 60-6; Van Blercom et al.,Clin Neuropharmacol. 2004, 27(3), 124-8; Cho et al., Biochem. Biophys.Res. Commun. 2006, 341, 6-12; Emborg, J Neuro. Meth. 2004, 139, 121-143;Tolwani et al., Lab Anim Sci 1999, 49(4), 363-71; Hirsch et al., JNeuralTransin Suppl 2003, 65, 89-100; Orth and Tabrizi, Mov Disord 2003,18(7), 729-37; Betarbet et al., Bioessays 2002, 24(4), 308-18; andMcGeer and McGeer, Neurobiol Aging 2007, 28(5), 639-647).

The efficacy of administering a compound of Formula (I) for treatingAlzheimer's disease may be assessed using animal and human models ofAlzheimer's disease and clinical studies. Useful animal models forassessing the efficacy of compounds for treating Alzheimer's disease aredisclosed, for example, in Van Dam and De Dyn, Nature Revs Drug Disc2006, 5, 956-970; Simpkins et al., Ann N YAcad Sci, 2005, 1052, 233-242;Higgins and Jacobsen, Behav Pharmacol 2003, 14(5-6), 419-38; Janus andWestaway, Physiol Behav 2001, 73(5), 873-86; Bardgett et al., Brain ResBull 2003, 60, 131-142; and Conn, ed., “Handbook of Models in HumanAging,” 2006, Elsevier Science & Technology.

The efficacy of administering a compound of Formula (I) for treatingHuntington's disease may be assessed using animal and human models ofHuntington's disease and clinical studies. Animal models of Huntington'sdisease are disclosed, for example, in Riess and Hoersten, U.S.Application Publication No. 2007/0044162; Rubinsztein, Trends inGenetics, 2002, 18(4), 202-209; Matthews et al., J. Neuroscience 1998,18(1), 156-63; Tadros et al., Pharmacol Biochem Behav 2005, 82(3),574-82, and in Kaddurah-Daouk et al., U.S. Pat. No. 6,706,764 and U.S.Application Publication Nos. 2002/0161049, 2004/0106680, and2007/0044162. An example of a placebo-controlled clinical trialevaluating the efficacy of creatine supplementation to treatHuntington's disease is disclosed in Verbessem et al., Neurology 2003,61, 925-230.

Treatment of bipolar disorder can be assessed in clinical trials usingrating scales such as the Montgomery-Asberg Depression Rating Scale, theHamilton Depression Scale, the Raskin Depression Scale, Feighnercriteria, and/or Clinical Global Impression Scale Score (Gijsman et al.,Am J Psychiatry 2004, 161, 1537-1547; and Post et al., J Clin Psychiatry2005, 66(3), 370-374).

Useful animal models for assessing treatment of anxiety includefear-potentiated startle (Brown et al., J Experimental Psychol 1951, 41,317-327); elevated plus-maze (Pellow et al., J Neurosci. Methods 1985,14, 149-167; and Hogg, Pharmacol Biochem Behavior 1996, 54(1), 21-20);fear-potentiated behavior in the elevated plus-maze test (Korte and DeBoer, Eur J Pharmacol 2003, 463, 163-175); X-maze test of anxiety(Handley and Mithani, Arch Pharmacol 1984, 327, 1-5); and rat socialinteraction test (File, J Neurosci Methods 1980, 2, 219-238). Geneticanimal models of anxiety are known (Toh, Eur J Pharmacol 2003, 463,177-184) as are other animal models sensitive to anti-anxiety agents(Martin, Acta Psychiatr Scand 1998, Suppl 393, 74-80).

In clinical trials, efficacy can be evaluated using psychologicalprocedures for inducing experimental anxiety applied to healthyvolunteers and patients with anxiety disorders (see e.g., Graeff, etal., Brazilian J Medical Biological Res 2003, 36, 421-32) or byselecting patients based on the Structured Clinical interview for DSM-IVAxis I Disorders as described by First et al., Structured ClinicalInterview for DSM-IV Axis I Disorders, Patient Edition (SCIDIP), Version2. Biometrics Research, New York State Psychiatric Institute, New York,1995. One or more scales can be used to evaluate anxiety and theefficacy of treatment including, for example, the Penn State WorryQuestionnaire (Behar et al., J Behav Ther Exp Psychiatry 2003, 34,25-43), the Hamilton Anxiety and Depression Scales, the SpielbergerState-Trait Anxiety Inventory, and the Liebowitz Social Anxiety Scale(Hamilton, J Clin Psychiatry 1980, 41, 21-24; Spielberger and Vagg, JPersonality Assess 1984, 48, 95-97; and Liebowitz, J Clin Psychiatry1993, 51, 31-35 (Suppl)).

The efficacy of compounds provided by the present disclosure fortreating depression can be evaluated in animal models of depression suchas the forced swim test (Porsolt et al., Nature 1977, 266, 525-532; andPorsolt et al., Arch Int Pharmacodyn 1997, 229, 327-336), the tailsuspension test (Cryan et al., Trends Pharmacol Sci 2002, 23, 238-245;and Cryan and Mombereau, Mol Psychiatr 2004, 9, 1050-1062), and well asother (Porsolt, Rev. Neurosci 2000, 11, 53-58).

Efficacy of tardive dyskinesia treatment can be assessed using animalmodels (Takeuchi et al., Prog Neuro-Psychopharmacol & Biol Psychiat1998, 22, 679-691; Abilio et al., Psychopharmacology 2002, 161, 340-347;Queiroz and Frussa-Filho, Prog Neuro-Psychopharmacol & Biol Psychiat1999, 23, 1405-1418; Andreassen et al., Br J Pharmacol 1996, 119(4),751-7; Dutra et al., Prog Neuro-Psychopharmacology & Biol Psychiatry2002, 26, 487-495; and Shoham, Brain Res 2004, 1004, 142-147).

The efficacy of a compound of Formula (I) for the treatment ofspasticity can be assessed using animal models of spasticity and inclinically relevant studies of spasticity of different etiologies. Thetherapeutic activity may be determined without determining a specificmechanism of action. Animal of spasticity are known (see e.g., Eaton, JRehab Res Dev 2003, 40(4), 41-54; Kakinohana et al., Neuroscience 2006,141, 1569-1583; Ligresti et al., British J Pharm 2006, 147, 83-91; Zhanget al., Chinese J Clin Rehab, 2006, 10(38), 150-151; Hefferan et al.,Neuroscience Letters 2006, 403, 195-200; and Li et al., J Neurophysiol2004, 92, 2694-2703). For example, animal models of spasticity include(a) the mutant spastic mouse (Chai et al., Proc. Soc. Exptl. Biol. Med.1962, 109, 491); (b) the acute/chronic spinally transected rat and theacute decerebrate rat (see e.g., Wright and Rang, Clin Orthop Relat Res1990, 253, 12-19; Shimizu et al., J Pharmacol Sci 2004, 96, 444-449; andLi et al., J Neurophysiol 2004, 92, 2694-2703); (c) primary observationIrwin Test in the rat (Irwin, Psychopharmacologia 1968, 13, 222-57); andd) Rotarod Test in the rat and mouse (Dunham et al., J. Am. Pharm.Assoc. 1957, 46, 208-09). Other animal models include spasticity inducedin rats following transient spinal cord ischemia (Kakinohana et al.,Neuroscience 2006, 141, 1569-1583; and Hefferan et al., NeuroscienceLetters 2006, 403, 195-200), spasticity in mouse models of multiplesclerosis (Ligresti et al., British J Pharmacol 2006, 147, 83-91); andspasticity in rat models of cerebral palsy (Zhang et al., Chinese J ClinRehabilitation 2006, 10(38), 150-151). The maximal electroshock seizure(MES) threshold test in rodents is sensitive for detecting potentialanticonvulsant properties (Losher and Schmidt, Epilepsy Res 1988,145-181). In this model, anticonvulsant agents elevate the threshold toelectrically-induced seizures while proconvulsants lower the seizurethreshold.

Methods of Administration and Doses

Methods for the treatment of diseases disclosed herein compriseadministering at least one compound of Formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of any of the foregoing, or a pharmaceuticalcomposition comprising any of the foregoing, to a patient in need ofsuch treatment.

A compound of Formula (I), a pharmaceutically acceptable salt thereof,or a pharmaceutically acceptable solvate of any of the foregoing, or apharmaceutical composition comprising any of the foregoing may beadministered by any appropriate route. Examples of suitable routes ofadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, inhalation, and topically. Administration may besystemic or local. Administration may be by bolus injection, continuousinfusion, or by absorption through epithelial or mucocutaneous linings,e.g., oral mucosa, rectal, and intestinal mucosa, etc. Administrationmay be systemic or local. In certain embodiments, a compound of Formula(I), or pharmaceutical composition thereof, is administered orally.

In certain embodiments, compounds of Formula (I) or pharmaceuticalcompositions thereof, are delivered to patients via sustained releasedosage forms, for example, via oral sustained release dosage forms, andin certain embodiments, are administered to a patient once or twice perday. When used to treat the diseases disclosed herein, a therapeuticallyeffective amount of one or more compounds of Formula (I) may beadministered or applied singly or in combination with other agents. Atherapeutically effective amount of one or more compounds of Formula (I)may also deliver a corresponding α-amino acid in combination withanother pharmaceutically active agent, including another compound ofFormula (I). For example, in the treatment of a patient suffering from aneuropsychiatric or neurodegenerative disorder, a dosage form comprisinga compound of Formula (I) may be administered in conjunction with atherapeutic agent known or believed to be capable of treating aneuropsychiatric or neurodegenerative disorder, at least one symptom ofa neuropsychiatric or neurodegenerative disorder, or at least onecondition associated with a neuropsychiatric or neurodegenerativedisorder.

The amount of a compound of Formula (I) that will be effective in thetreatment of a disease disclosed herein in a patient will depend, inpart, on the nature of the condition and may be determined by standardclinical techniques known in the art. In addition, in vitro and in vivoassays may be employed to help identify optimal dosage ranges. Atherapeutically effective amount of prodrug of Formula (I) to beadministered may also depend on, among other factors, the subject beingtreated, the weight of the subject, the severity of the diseasedisclosed herein, the manner of administration, and the judgment of theprescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a beneficial circulatingcomposition concentration range. Initial doses may also be estimatedfrom in vivo data, e.g., animal models, using techniques that are knownin the art. Such information can be used to more accurately determineuseful doses in humans. One having ordinary skill in the art canoptimize administration doses to humans based on animal data.

In some embodiments, oral sustained release dosage forms are adapted tobe administered to a patient 1-3 times per day. In some embodiments, anoral sustained release dosage forms are adapted to be administered to apatient 1-2 times per day. In some embodiments, an oral sustainedrelease dosage form is adapted to be administered once per day. Dosingmay be provided alone or in combination with other drugs and maycontinue as long as required for effective treatment of a diseasedisclosed herein.

Suitable dosage ranges for oral administration are dependent on thepotency of the particular α-amino acid (once cleaved from the promoiety)but may range from about 0.1 mg to about 200 mg of drug per kilogrambody weight per day, for example, from about 1 to about 100 mg/kg-bodywt per day. In certain embodiments, a compound of Formula (I) isadministered to a patient in an amount ranging from about 10mg-equivalents to about 3600 mg-equivalents of the corresponding α-aminoacid per day, in certain embodiments, ranging from about 200mg-equivalents to about 2400 mg-equivalents of the corresponding α-aminoacid per day, and in certain embodiments, ranging from about 400mg-equivalents to about 1600 mg-equivalents of the corresponding α-aminoacid per day, to treat a disease disclosed herein. Dosage amounts andranges may be readily determined by methods known to those skilled inthe art.

A dose may be administered in a single dosage form or in multiple dosageforms. When multiple dosage forms are used, the amount of compoundcontained within each dosage form may be the same or different. Theamount of a compound of Formula (I) contained in a dose may depend onthe route of administration and whether the disease to be treated in apatient is effectively treated by acute, chronic, or a combination ofacute and chronic administration.

In certain embodiments, an administered dose is less than a toxic dose.Toxicity of the compositions described herein may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) or the LD₁₀₀ (the dose lethal to 100% of the population).The dose ratio between toxic and therapeutic effect is the therapeuticindex. In certain embodiments, the pharmaceutical compositions exhibit ahigh therapeutic index. The data obtained from these cell culture assaysand animal studies may be used in formulating a dosage range that is nottoxic for use in humans. Doses of a pharmaceutical compositioncomprising a compound of Formula (I) may be within a range ofcirculating concentrations in, for example, the blood, plasma, andcentral nervous system, that include the effective dose and that exhibitlittle or no toxicity. A dose may vary within this range depending uponthe dosage form employed and the route of administration utilized. Incertain embodiments, an escalating dose is administered.

The efficacy of administering a compound of Formula (I) for treating adisease disclosed herein may be assessed using animal and human modelsof the diseases disclosed herein and with clinical results.

During treatment, a dose and dosing schedule may provide sufficient orsteady state levels of an effective amount of an α-amino acid to treat adisease. In certain embodiments, an escalating dose is administered.

In certain embodiments, oral administration of an oral sustained releasedosage form comprising a compound of Formula (I) provides atherapeutically effective concentration of an α-amino acid in the bloodplasma of a patient for a time period of at least about 4 hours afteradministration of the dosage form, in certain embodiments, for a timeperiod of at least about 8 hours, and in certain embodiments, for a timeperiod of at least about 12 hours.

Combination Therapy

Compounds of Formula (I) may be used in combination with one or moreother therapeutic agents in the treatment of diseases or disorders forwhich compounds of Formula (I) or the other therapeutic agents haveutility, where the combination of the drugs together are safer or moreeffective than either drug alone. Such other drug(s) may beadministered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of Formula (I). When acompound of Formula (I) is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchother drugs and the compound of Formula (I) may be used. However, thecombination therapy may also include therapies in which the compound ofFormula (I) and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active agents, compounds of Formula(I) and the other active agents may be used in lower doses than wheneach is used singly. Accordingly, pharmaceutical compositions providedby the present disclosure include those that comprise one or more otheractive therapeutic agents, in addition to a compound of Formula (I).

The above combinations may include combinations of a compound of Formula(I) not only with one other active compound, but also with two or moreother active compounds. Likewise, compounds of Formula (I) may be usedin combination with other drugs that are used in the treatment of thediseases or conditions for which compounds of Formula (I) are useful.Such other drugs may be administered, by a route and in an amountcommonly used therefore, contemporaneously or sequentially with acompound of Formula (I). When a compound of Formula (I) is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofFormula (I) may be used. Accordingly, the pharmaceutical compositions ofthe present disclosure include those that also contain one or more otheractive agents, in addition to a compound of Formula (I).

In certain embodiments, a compound of Formula (I), or pharmaceuticallyacceptable salt, or pharmaceutically acceptable solvate of any of theforegoing, may be used in combination therapy with at least one othertherapeutic agent. A compound of Formula (I) and other therapeuticagent(s) may act additively or, and in certain embodiments,synergistically. In some embodiments, a compound of Formula (I) may beadministered concurrently with the administration of another therapeuticagent. In some embodiments, the compound of Formula (I), apharmaceutically acceptable salt, or a pharmaceutically acceptablesolvate of any of the foregoing is administered prior or subsequent toadministration of another therapeutic agent. Pharmaceutical compositionsprovided by the present disclosure may include, in addition to one ormore compounds of Formula (I), one or more therapeutic agents effectivefor treating the same or different disease, disorder, or condition.Methods provided by the present disclosure include administration of oneor more compounds of Formula (I) or pharmaceutical compositionscomprising a compound of Formula (I) and one or more other therapeuticagents provided that the combined administration does not inhibit thetherapeutic efficacy of the one or more compounds of Formula (I) and/ordoes not produce adverse combination effects.

In certain embodiments, compositions comprising a compound of Formula(I) are administered concurrently with the administration of anothertherapeutic agent, which may be part of the same pharmaceuticalcomposition or dosage form as, or may be in a different composition ordosage form from, that containing the compounds of Formula (I). Incertain embodiments, compounds of Formula (I) are administered prior orsubsequent to administration of another therapeutic agent. In certainembodiments of combination therapy, the combination therapy comprisesalternating between administering a composition comprising a compound ofFormula (I) of the present disclosure and a composition comprisinganother therapeutic agent, e.g., to minimize adverse side effectsassociated with a particular drug. When a compound of Formula (I) isadministered concurrently with another therapeutic agent thatpotentially may produce adverse side effects including, but not limitedto, toxicity, the therapeutic agent may be administered at a dose thatfalls below the threshold at which the adverse side effect is elicited.

The weight ratio of a compound of Formula (I) to the second therapeuticagent may vary and depends upon the effective dose of each agent.Generally, a therapeutically effective dose of each compound will beused. Thus, for example, when a compound of Formula (I) is combined withanother therapeutic agent, the weight ratio of the compound of Formula(I) to the second therapeutic agent may range from about 1000:1 to about1:1000, and in certain embodiments, from about 200:1 to about 1:200.

Combinations of a compound of Formula (I) and a second therapeutic agentmay also be within the aforementioned range, but in each case, aneffective dose of each active compound may be used. In such combinationsthe compound of Formula (I) and the second therapeutic agent may beadministered separately or in conjunction. In addition, theadministration of one compound may be prior to, concurrent with, orsubsequent to the administration of another therapeutic agent(s).Accordingly, compounds of Formula (I) may be used alone or incombination with other therapeutic agents that are known to bebeneficial in the subject indications or other therapeutic agents thataffect receptors or enzymes that either increase the efficacy, safety,convenience, or reduce unwanted side effects or toxicity of thecompounds of Formula (I). A compound of Formula (I) and the othertherapeutic agent may be co-administered, either in concomitant therapyor in a fixed combination. In certain embodiments, the compound ofFormula (I) may be employed in combination with anti-Alzheimer's agents,beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductaseinhibitors, NSAIDs including ibuprofen, vitamin E, and anti-amyloidantibodies, and combinations thereof.

In certain embodiments, a compound of Formula (I) is administered incombination with an antipsychotic, an antidepressant, an anxiolytic, ananti-anxiety agent, sedatives, or a hypnotic.

In certain embodiments, a compound of Formula (I) may be administered incombination with sedatives, hypnotics, anxiolytics, antipsychotics,anti-anxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as, for example, adinazolam,allobarbital, alonimid, alprazolam, amisulpride, amitriptyline,amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine,brotizolam, bupropion, busprione, butabarbital, butalbital, capuride,carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam,cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine,clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol,fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam,glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium,lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin,mephobarbital, meprobamate, methaqualone, midaflur, midazolam,nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam,paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine,phenelzine, phenobarbital, prazepam, promethazine, propofol,protriptyline, quazepam, quetiapine, reclazepam, risperidone,roletamide, secobarbital, sertraline, suproclone, temazepam,thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,ziprasidone, zolazepam, zolpidem, salts of any of the foregoing, orcombinations of any of the foregoing, or a compound of Formula (I) maybe administered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In certain embodiments, a compound of Formula (I) is administered incombination with levodopa (with or without a selective decarboxylaseinhibitor such as carbidopa or benserazide), an anti-cholinergic such asbiperiden and trihexyphenidyl (benzhexyl)hydrochloride,catechol-O-methyltransferase (COMT) inhibitors such as entacapone,monoamine oxidase-B (MOA-B) inhibitors, antioxidants, A2a adenosinereceptor antagonists, cholinergic agonists, serotonin receptorantagonists, or dopamine receptor agonists such as alentemol,bromocriptine, fenoldopam, lisuride, naxagolide, pergolide, pramipexole,ropinirole, and rotigotine, pharmaceutically acceptable salts of any ofthe foregoing, or combinations of any of the foregoing.

In certain embodiments, a compound of Formula (I) is administered incombination with a compound chosen from a phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine, andindolone classes of neuroleptic agents. Examples of usefulphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine, and trifluoperazine.Examples of useful thioxanthenes include chlorprothixene andthiothixene. An example of a useful dibenzazepine is clozapine. Anexample of a useful butyrophenone is haloperidol. An example of a usefuldiphenylbutylpiperidine is pimozide. An example of a useful indolone ismolindolone. Other neuroleptic agents include loxapine, sulpiride, andrisperidone. It will be appreciated that the neuroleptic agents whenused in combination with a compound of Formula (I) may be in the form ofa pharmaceutically acceptable salt. In certain embodiments, a compoundof Formula (I) is administered in combination with acetophenazine,alentemol, aripiprazole, amisulpride, benzhexyl, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine,trihexyphenidyl, thioridazine, thiothixene, trifluoperazine,ziprasidone, pharmaceutically acceptable salts of any of the foregoing,or combinations of any of the foregoing.

In certain embodiments, a compound of Formula (I) is administered incombination with an antipsychotic drug chosen from haloperidol,chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, trifluoperazine, clozapine, risperidone, olanzapine,quetiapine, ziprasidone, aripiprazole, and sertindole.

In certain embodiments, a compound of Formula (I) is administered incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors such as tertiary amine tricyclics,and secondary amine tricyclics, selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase, serotonin and noradrenaline reuptake inhibitors(SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, or 5-HT-IA agonists orantagonists, especially 5-HT-IA partial agonists, and corticotropinreleasing factor (CRF) antagonists. Examples of anti-depressant and/oranti-anxiety agents include amitriptyline, clomipramine, doxepin,imipramine, trimipramine, amoxapine, desipramine, maprotiline,nortriptyline, protriptyline, fluoxetine, fluvoxamine, paroxetine,sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline,moclobemide, venlafaxine, duloxetine, aprepitant, bupropion, lithium,nefazodone, trazodone, viloxazine, alprazolam, chlordiazepoxide,clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam,prazepam, buspirone, flesinoxan, gepirone, ipsapirone, pharmaceuticallyacceptable salts of any of the foregoing, or combinations of any of theforegoing.

In certain embodiments, a compound of Formula (I) is administered incombination with a compound useful for treating at least one ofschizophrenia, bipolar disorder, depression including unipolardepression, seasonal depression and post-partum depression, premenstrualsyndrome (PMS) and premenstrual dysphoric disorder (PDD), a learningdisorder, pervasive developmental disorder including autistic disorder,an attention disorder including Attention-Deficit/HyperactivityDisorder, autism, a tic disorder including Tourette's disorder, ananxiety disorder including phobia and post-traumatic stress disorder,cognitive disorders associated with dementia, AIDS dementia, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, spasticity,myoclonus, muscle spasm, tinnitus, and hearing impairment or loss.

Examples of drugs useful for treating psychotic disorders includechlorpromazine, clozapine, fluphenazine, haloperidol, olanzapine,perphenazine, prochlorperazine, risperidone, and thiothixene. Examplesof drugs useful for treating schizophrenia include apriprazole,loxapine, mesoridazine, quetiapine, reserpine, thioridazine,trifluoperazine, and ziprasidone. Examples of drugs useful for treatingbipolar disorder include carbamazepine, clonazepam, clonidine, valproicacid, and verapamil. Examples of drugs useful for treating depressioninclude alprazolam, amitriptyline, amoxapine, bupropion, citalopram,clomipramine, desipramine, doxepin, escitalopram, fluoxetine,fluvoxamine, imipramine, maprotiline, methylphenidate, mirtazapine,nefazodone, nortriptyline, paroxetine, protriptyline, sertraline,trazodone, and venlafaxine. Examples of drugs useful for treatingpremenstrual dysphoric disorder include fluoxetine, paroxetine, andsertraline. Examples of drugs useful for treating attention deficitdisorder include amphetamine-dextroamphetamine, atomoxetine, bupropion,dexmethylphenidate, dextroamphetamine, methamphetamine, methylphenidate,and pemoline. Examples of drugs useful for treating Tourette's syndromeinclude haloperidol, pergolide, and pimozide. Examples of drugs usefulfor treating anxiety disorders include alprazolam, atenolol, gusiprone,chlordiazepoxide, clonidine, clorazepate, diazepam, doxepin,escitalopram, halazepam, hydroxyzine, lorazepam, nadolol, oxazepam,paroxetine, prochlorperazine, trifuoperazine, and venlafaxine. Examplesof drugs useful for treating post-traumatic stress disorder includeamitriptyline and sertraline. Examples of drugs useful for treatingdementia include haloperidol. Examples of drugs useful for treatingAlzheimer's disease include donepezil, galantamine, memantine,rivastigmine, and tacrine. Examples of drugs useful for treatingParkinson's disease include amantadine, benztropine, bromocriptine,carbidopa and levodopa, pergolide, pramipexole, ropinirole, selegiline,and trihexyphenidyl.

EXAMPLES

The following examples describe in detail preparation of compounds ofFormula (I), methods of assessing compounds of Formula (I). It will beapparent to those skilled in the art that many modifications, both tomaterials and methods, may be practiced without departing from the scopeof the disclosure.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

DMSO=dimethylsulfoxide

HPLC=high pressure liquid chromatography

LC/MS=liquid chromatography/mass spectroscopy

M=molar

mL=milliliter

mM millimolar

mmol=millimoles

μg=microgram

μL=microliter

μM=micromolar

v/v=volume to volume

General Experimental Protocols

O-(1-Acyloxyalkyl) S-alkylthiocarbonates are synthesized according tothe procedures disclosed in Gallop et al., U.S. Application PublicationNo. 2005/0222431 (which is incorporated herein by reference in itsentirety) and converted to the corresponding acyloxyalkylN-hydroxysuccinimide carbonic acid esters as described therein, oraccording to the general procedure given below. All other reagents andsolvents are purchased from commercial suppliers and used withoutfurther purification or manipulation.

Proton NMR spectra (400 MHz) are recorded on a Varian AS 400 NMRspectrometer equipped with an autosampler and data processingcomputation. DMSO-d⁶ (99.9% D) or CDCl₃ (99.8% D) are used as solventsunless otherwise noted. The DMSO or chloroform solvent signal is usedfor calibration of the individual spectra (H. E. Gottlieb et al., J.Org. Chem., 1997, 62, 7512). Analytical LC/MS is performed on a Waters2790 separation module equipped with a Waters Micromass QZ massspectrometer, a Waters 996 photodiode detector, and a Merck ChromolithUM2072-027 or Phenomenex Luna C-18 analytical column. Mass-guidedpreparative HPLC purification of final compounds is performed on aninstrument equipped with a Waters 600 controller, ZMD Micromassspectrometer, a Waters 2996 photodiode array detector, and a Waters 2700Sample Manager. Acetonitrile/water gradients containing 0.05% formicacid are used as eluents in both analytical and preparative HPLCexperiments.

General Procedure for the Synthesis of Acyloxyalkyl N-hydroxysuccinimideCarbonic Acid Esters

A 250 mL round-bottomed flask equipped with a magnetic stir bar and apressure-equilibrating dropping funnel was charged with 1-acyloxyalkylalkylthiocarbonate (10 mmol) and N-hydroxysuccinimide (20-40 mmol).Dichloromethane (20-40 mL) was added and the reaction mixture cooled toca. 0° C. in an ice bath. Peracetic acid (32 wt.-%) in a 40-45% aqueousacetic acid solution (30 mmol) was added drop wise to the cooledsolution while stirring over a period of ca. one hour. After theaddition was complete, the mixture is stirred for an additional three tofive hours, and the reaction monitored using ¹H NMR spectroscopy. Afterthe starting material was completely, the reaction mixture was dilutedwith additional dichloromethane, and the organic solution washedsuccessively with water (three times) and once with a 10% aqueoussolution of sodium metabisulfite or sodium thiosulfate to quench anyremaining oxidant. The combined organic extracts were dried over MgSO₄,filtered, and the solvent removed under reduced pressure with a rotaryevaporator. Compound identity, integrity, and purity were determinedusing ¹H NMR spectroscopy. The crude material was used directly in thenext step, or was further purified using methods well known to thoseskilled in the art.

General Procedure for Synthesis of Acyloxyalkyl Carbamates of α-AminoAcids

A screw-capped 40 mL glass vial equipped with a magnetic stir bar wascharged with an aqueous solution (5 mL) of an appropriate α-amino acid(2 mmol). The appropriate acyloxyalkyl N-hydroxysuccinimide carbonicacid ester (2 mmol) was added either as a solid or dissolved in a smallvolume of solvent (for oily materials). A mixture of acetonitrile andwater (v/v=1:1) (15-20 mL) was added, and the reaction mixture stirredfor ca. 12 hours at room temperature. Upon completion of the reaction,the mixture was diluted with ethyl acetate and 1N aqueous hydrochloricacid (ca. 10 mL). After vigorous mixing followed by phase separation,the aqueous layer was extracted once more with EtOAc, and the combinedorganic extracts were washed with brine. The solvents were evaporatedunder reduced pressure, the dry residue dissolved in a mixture of 60%(v/v) acetonitrile/water, and the solution filtered through a 0.2 μmnylon syringe filter. Final purification was done using mass-guidedpreparative HPLC. After lyophilization of the solvents, the purecompounds were obtained as a white powder or colorless wax.

General Procedure for One Pot Synthesis of Acyloxyalkyl Carbamates ofα-Amino Acids

Under an atmosphere of nitrogen, a dry 100 mL round-bottomed flaskequipped with a magnetic stir bar and a rubber septum was charged with1-aminocyclopropane-1-carboxylic acid (ACPC) (11.2 mmol). Anhydrouschloroform (10-15 mL) was added, and the reaction mixture cooled to ca.0° C. in an ice bath. Neat chlorotrimethylsilane (22.4 mmol) was addedat this temperature, followed by the slow addition ofdiisopropylethylamine (DIEA) (22.4 mmol). The reaction mixture wasstirred at this temperature for ca. 30 min, at which time anappropriately substituted chloroalkylchloroformate (13.44 mmol) wasadded drop wise and in neat form. After the addition, the reactionmixture was warmed to ca. room temperature and stirred at thistemperature for an additional 1 hour. A premixed mixture of DIEA (22.4mmol) and an appropriately substituted carboxylic acid (22.4 mmol) wasadded at ca. room temperature. The reaction mixture was stirredovernight at 50° C. The chloroform was removed in vacuo using a rotaryevaporator. The crude reaction product was diluted with methyltert-butyl ether (MTBE), and the solution washed three times with water.The organic layer was dried over MgSO₄, and the filtrate evaporated invacuo using a rotary evaporator. The crude dry residue was dissolved ina small amount of a mixture of 60% (v/v) acetonitrile/water (ca. 5 mL)and the solution filtered through a 0.2 μm nylon syringe filter. Finalpurification was done using mass-guided preparative HPLC. Afterlyophilization of the solvents, the pure compounds were generallyobtained as solids or waxy materials.

Many of the chloroformates were commercially available and otherschloroformates were synthesized following the procedure according toCoghlan and Caley, Tetrahedron Letters 1989, 30(16), 2033-2036.

Example 1 1-(1-Isobutyryloxy-ethoxycarbonylamino)-cyclopropanecarboxylicAcid (1)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (121 mg, 1.2 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylpropanoate (273 mg, 1.0mmol) were reacted to provide 123 mg (47% yield) of the title compound(1) as a white powder after work-up and mass-guided preparative HPLCpurification. M.p.: 127.0-129.5° C. ¹H NMR (CDCl₃, 400 MHz): δ=6.79 (q,1H), 6.05 (br s, 0.2H), 5.41 (s, 0.8H), 2.52 (m, 1H), 1.61 (m, 2H), 1.48(d, 3H), 1.28 (m, 2H), 1.18 (d, 6H). MS (ESI) m/z 277.17 (M+NH₄)⁺;282.12 (M+Na)⁺; 258.13 (M−H)⁻.

Example 21-(1-Isobutyryloxy-2-methyl-propoxycarbonylamino)-cyclopropanecarboxylicAcid (2)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (121 mg, 1.2 mmol) and1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanoate(301 mg, 1.0 mmol) were reacted to provide 148 mg (51% yield) of thetitle compound (2) as a white powder after work-up and mass-guidedpreparative HPLC purification. M.p.: 127.4-129.0° C. ¹H NMR (CDCl₃, 400MHz): δ=6.59 (d, 1H), 5.68 (br s, 0.3H), 5.39 (s, 0.7H), 2.58 (m, 1H),2.01 (m, 1H), 1.61 (m, 2H), 1.30 (m, 2H), 1.19 (d, 3H), 1.18 (d, 3H),0.99 (d, 6H). MS (ESI) m/z 305.20 (M+NH₄)⁺; 310.15 (M+Na)⁺; 286.21(M−H)⁻.

Example 31-{[(2-Methylphenylcarbonyloxy)ethoxy]carbonylamino}cyclopropanecarboxylicAcid (3)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (121 mg, 1.2 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylbenzoate (321 mg, 1.0mmol) were reacted to provide 133 mg (43% yield) of the title compound(3) as a white powder after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CDCl₃, 400 MHz): δ=7.85 (d, 1H), 7.40 (t, 1H),7.21 (t, 2H), 7.01 (q, 1H), 5.79 (br s, 0.3H), 5.41 (s, 0.7H), 2.58 (s,3H), 1.60 (m, 5H), 1.30 (m, 2H). MS (ESI) m/z 325.17 (M+NH₄)⁺; 330.12(M+Na)⁺; 306.15 (M−H)⁻.

Example 41-[(Phenylcarbonyloxyethoxy)carbonylamino]cyclopropanecarboxylic Acid(4)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (121 mg, 1.1 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl benzoate (341 mg, 1.0 mmol)were reacted to provide 113 mg (35% yield) of the title compound (4) asa white powder after work-up and mass-guided preparative HPLCpurification. M.p.: 173.8-175.8° C. ¹H NMR (CD₃CN, 400 MHz): δ=8.00 (d,2H), 7.61 (t, 1H), 7.50 (t, 2H), 6.99 (q, 1H), 6.31 (s, 0.8H), 6.01 (brs, 0.2H), 1.60 (d, 3H), 1.42 (m, 2H), 1.09 (m, 2H). MS (ESI) m/z 294.10(M+H)⁺; 311.12 (M+NH₄)⁺; 316.11 (M+Na)⁺; 292.12 (M−H)⁻.

Example 51-[1-(3-Methyl-butyryloxy)-ethoxycarbonylamino]-cyclopropanecarboxylicAcid (5)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (121 mg, 1.2 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 3-methylbutanoate (287 mg, 1.0mmol) were reacted to provide 78 mg (28% yield) of the title compound(5) as a white powder after work-up and mass-guided preparative HPLCpurification. M.p.: 116.6-119.1° C. ¹H NMR (CDCl₃, 400 MHz): δ=6.80 (q,1H), 6.05 (br s, 0.2H), 5.42 (s, 0.8H), 2.01-2.22 (m, 3H), 1.61 (m, 2H),1.48 (d, 3H), 1.25 (m, 2H), 0.98 (d, 6H). MS (ESI) m/z 291.18 (M+NH₄)⁺;296.13 (M+Na)⁺; 272.14 (M−H)⁻.

Example 61-[1-(2,2-Dimethyl-propionyloxy)-ethoxycarbonylamino]-cyclopropanecarboxylicAcid (6)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (364 mg, 3.6 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2,2-dimethylpropanoate (862 mg,3.0 mmol) were reacted to provide 472 mg (58% yield) of the titlecompound (6) as a white powder after work-up and mass-guided preparativeHPLC purification. ¹H NMR (CDCl₃, 400 MHz): δ=10.29 (br s, 1H), 6.68 (q,1H), 6.41 (br s, 0.3H), 5.60 (s, 0.7H), 1.60 (m, 2H), 1.42 (m, 3H), 1.19(s, 9H). MS (ESI) m/z 291.10 (M+NH₄)⁺; 296.08 (M+Na)⁺; 272.08 (M−H)⁻.

Example 7 1-(1-Butyryloxy-ethoxycarbonylamino)-cyclopropanecarboxylicAcid (7)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (121 mg, 1.2 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl butanoate (273 mg, 1.0 mmol)were reacted to provide 61 mg (24% yield) of the title compound (7) as awhite powder after work-up and mass-guided preparative HPLCpurification. M.p.: 90.4-93.4° C. ¹H NMR (CDCl₃, 400 MHz): δ=9.31 (br s,1H), 6.80 (q, 1H), 6.20 (br s, 0.2H), 5.47 (s, 0.8H), 2.28 (m, 2H),1.51-1.70 (m, 4H), 1.48 (d, 3H), 1.25 (m, 2H), 0.98 (t, 3H). MS (ESI)m/z 277.17 (M+NH₄)⁺; 282.12 (M+Na)⁺.

Example 8 1-(1-Pentanoyloxy-ethoxycarbonylamino)-cyclopropanecarboxylicAcid (8)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (121 mg, 1.2 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl pentanoate (287 mg, 1.0 mmol)were reacted to provide 153 mg (56% yield) of the title compound (8) asa white powder after work-up and mass-guided preparative HPLCpurification. M.p.: 148.0-151.1° C. ¹H NMR (CDCl₃, 400 MHz): δ=6.80 (q,1H), 5.80 (br s, 0.2H), 5.40 (s, 0.8H), 2.31 (m, 2H), 1.52-1.70 (m, 4H),1.47 (d, 3H), 1.20-1.40 (m, 4H), 0.91 (t, 3H). MS (ESI) m/z 291.15(M+NH₄)⁺; 296.12 (M+Na)⁺; 272.12 (M−H)⁻.

Example 9 1-Isobutyryloxymethoxycarbonylaminocyclopropanecarboxylic Acid(9)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (121 mg, 1.2 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)methyl 2-methylpropanoate (259 mg,1.0 mmol) were reacted to provide 107 mg (44% yield) of the titlecompound (9) as a white powder after work-up and mass-guided preparativeHPLC purification. ¹H NMR (CDCl₃, 400 MHz): δ=5.99 (br s, 0.2H), 5.78(br s, 0.4H), 5.73 (s, 1.6H), 5.59 (s, 0.8H), 2.59 (m, 1H), 1.62 (m,2H), 1.31 (m, 2H), 1.19 (d, 6H). MS (ESI) m/z 246.10 (M+H)⁺; 263.11(M+NH₄)⁺; 268.09 (M+Na)⁺; 244.11 (M−H)⁻.

Example 101-[(Cyclohexylcarbonyloxyethoxy)carbonylamino]cyclopropanecarboxylicAcid (10)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (426 mg, 4.2 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl cyclohexanecarboxylate (1.1 g,3.5 mmol) were reacted to provide 172 mg (16% yield) of the titlecompound (10) as a white powder after work-up and mass-guidedpreparative HPLC purification. M.p.: 123.6-125.3° C. ¹H NMR (CDCl₃, 400MHz): δ=9.92 (br s, 1H), 6.76 (q, 1H), 6.34 (br s, 0.3H), 5.59 (s,0.7H), 2.27 (m, 1H), 1.10-1.95 (m, 17H). MS (ESI) m/z 317.15 (M+NH₄)⁺;322.13 (M+Na)⁺; 298.15 (M−H)⁻.

Example 111-[(1-Cyclohexylcarbonyloxy-2-methylpropoxy)carbonylamino]cyclopropanecarboxylicAcid (II)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (0.533 g, 5.27 mmol) and1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropylcyclohexanecarboxylate (1.5 g, 4.39 mmol) were reacted in theacetonitrile/water mixture to provide 0.368 g (27% yield) of the titlecompound (11) as a white powder after work-up and mass-guidedpreparative HPLC purification. M.p.: 156-158.5° C. ¹H NMR (CDCl₃, 400MHz): δ=6.59 (d, 1H), 6.05 (br s, 0.3H), 5.41 (s, 0.7H), 2.38 (m, 1H),2.13 (m, 1H), 1.96 (d. 2H), 1.78 (m, 2H), 1.6 (m, 3H), 1.44 (m, 2H),1.23 (m, 5H), 0.99 (m, 6H). MS (ESI) m/z 350.05 (M+Na)⁺.

Example 121-[(2-Methyl-1-phenylcarbonyloxypropoxy)carbonylamino]cyclopropanecarboxylicAcid (12)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (0.726 g, 7.15 mmol) and1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl benzoate (2 g, 5.96mmol) were reacted in the acetonitrile/water mixture to provide 0.445 g(25% yield) of the title compound (12) as a white powder after work-upand mass-guided preparative HPLC purification. ¹H NMR (CDCl₃, 400 MHz):δ=8.02 (d, 2H), 7.59 (t, 1H), 7.42 (t, 2H), 6.82 (d, 1H), 5.56 (br s.0.3H), 5.44 (s, 0.7H), 2.21 (m, 1H), 1.61 (m, 2H), 1.39 (m, 2H), 1.02(dd, 6H). MS (ESI) m/z 344.19 (M+Na)⁺.

Example 13 1-[(Heptanoyloxyethoxy)carbonylamino]cyclopropanecarboxylicAcid (13)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (0.530 g, 5.2 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl heptanoate (1 g, 4.03 mmol)were reacted to provide 0.148 g (15.4% yield) of the title compound (13)as a white powder after work-up and mass-guided preparative HPLCpurification. M.p.: 112.6-113.2° C. ¹H NMR (CDCl₃, 400 MHz): δ=6.79 (q,1H), 5.81 (s, 0.2H), 5.4 (s, 0.8H), 2.3 (m, 2H), 1.64 (m, 4H), 1.51 (d,3H), 1.32 (m, 8H), 0.98 (t, 3H). MS (ESI) m/z 324.05 (M+Na)⁺; 300.04(M−H)⁻.

Example 141-{[(3,4-Dimethoxyphenylcarbonyloxy)ethoxy]carbonylamino}cyclopropanecarboxylicAcid (14)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (0.122 g, 1.21 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 3,4-dimethoxybeanzoate (0.4 g,1.01 mmol) were reacted to provide 0.260 g (68% yield) of the titlecompound (14) as a white powder after work-up and mass-guidedpreparative HPLC purification. M.p.: 171.8-173.6° C. ¹H NMR (CDCl₃, 400MHz): δ=7.69 (d, 1H), 7.47 (s, 1H), 7.13 (d, 1H), 6.83 (d, 1H), 5.52 (s,0.3H), 5.43 (s, 0.7H), 3.98 (d, 6H), 1.62 (m, 5H), 1.31 (br s, 2H). MS(ESI) m/z 375.99 (M+Na)⁺; 352.02 (M−H)⁻.

Example 151-{[(4-Phenylbutanoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylicAcid (15)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, ACPC (0.218 g, 2.08 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 4-phenylbutyrate (0.607 g, 1.73mmol) were reacted to provide 0.264 g (46% yield) of the title compound(15) as a white semi-solid after work-up and mass-guided preparativeHPLC purification. ¹H NMR (CDCl₃, 400 MHz): δ=7.32 (t, 2H), 7.19 (m,3H), 6.81 (q, 1H), 6.22 (s, 0.3H), 5.43 (s, 0.7H), 2.62 (t, 2H), 2.31(m, 2H), 1.98 (q, 2H), 1.61 (m, 2H), 1.42 (dd, 3H), 1.23 (m, 2H). MS(ESI) m/z 358.05 (M+Na)⁺.

Example 161-{[((2E)-3-Phenylprop-2-enoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylicAcid (16)

Following the general procedure for the one pot synthesis, ACPC (0.4 g,3.9 mmol) was reacted with chlorotrimethylsilane (0.99 mL, 7.88 mmol) inanhydrous chloroform (10 mL) in the presence of DIEA (1.45 mL, 7.8mmol). Subsequent reaction of the intermediate with1-chloroethylchloroformate (0.83 mL, 5.85 mmol) followed by a mixture ofDIEA (1.45 mL, 7.8 mmol) and trans-cinnamic acid (1.16 g, 7.88 mmol)provided 0.200 g (16.6% yield) of the title compound (16) as abuff-colored solid after aqueous work-up and mass-guided preparativeHPLC purification. M.p: 169.3-172.2° C. ¹H NMR (CDCl₃, 400 MHz):δ=7.71-7.67 (d, 1H, J=15.6), 7.50 (d, 2H), 7.38 (m, 3H), 6.95 (q, 1H),6.40 (d, 1H, J=16), 5.58 (s, 0.3H), 5.34 (s, 0.7H), 1.60-1.54 (m, 5H),1.27-1.24 (m, 2H). MS (ESI) m/z 342.00 (M+Na)⁺; 318.02 (M−H)⁻.

Example 171-{[(3-Phenylpropanoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylicAcid (17)

A dry 100 mL round-bottomed flask equipped with a magnetic stir bar anda rubber septum was charged with1-{[((2E)-3-phenylprop-2-enoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylicacid (16) (0.8 g, 2.5 mmols) and 10% palladium on carbon in 1:1 mixtureof ethylacetate and ethanol. The reaction was done at 1 atm pressureunder a hydrogen balloon at room temperature. After the reaction wascomplete, the solution was filtered through Celite and the solventsremoved in vacuo using a rotary evaporator. The dry, crude residue wasdissolved in a small amount of a mixture of 60% (v/v) acetonitrile/water(ca. 10 mL), and the solution filtered through a 0.2 μm nylon syringefilter. Final purification was achieved by mass-guided preparative HPLC.After lyophilization of the solvents, 0.646 g (80% yield) of the titlecompound (17) was obtained as a white solid. M.p: 132.9-134.4° C. ¹H NMR(CDCl₃, 400 MHz): δ=7.31 (t, 2H), 7.19 (t, 3H), 6.82 (q, 11H), 6.38 (s,0.3H), 5.50 (s, 0.7H), 2.99 (t, 2H), 2.72 (m, 2H), 1.71 (m, 2H), 1.42(d, 3H), 1.30 (m, 2H). MS (ESI) m/z 343.93 (M+Na)⁺, 319.96 (M−H)⁻.

Example 181-{[1-((2E)-3-Phenylprop-2-enoyloxy)-2-methylpropoxy]carbonylamino}cyclopropanecarboxylicAcid (18)

Following the general procedure for the one pot synthesis, ACPC (2.5 g,24.6 mmol) was reacted with chlorotrimethylsilane (6.25 mL, 49.2 mmol)in anhydrous chloroform (25 mL) in the presence of DIEA (9.1 mL, 49.4mmol). Subsequent reaction of the intermediate with1-chloro-2-methylpropyl chloroformate (5.0 mL, 37 mmol) followed by amixture of DIEA (9.1 mL, 49.4 mmol) and trans-cinnamic acid (7.1 g, 48mmol) provided 0.406 g (12.2% yield) of the title compound (18) as alight-yellow solid after aqueous work-up and mass-guided preparativeHPLC purification. M.p: 147.8-150.2° C. ¹H NMR (CDCl₃, 400 MHz):δ=7.72-7.68 (d, 1H, J=15.6), 7.51 (br s, 2H), 7.37 (m, 3H), 6.71 (d,1H), 6.42 (d, 1H, J=16), 5.51 (s, 0.3H), 5.31 (s, 0.7H), 2.11 (m, 1H),1.58 (m, 2H), 1.24 (m, 2H), 1.02 (d, 6H). MS (ESI) m/z 345.98 (M−H)⁻.

Example 191-{[2-Methyl-1-(3-phenylpropanoyloxy)propoxy]carbonylamino}cyclopropanecarboxylicAcid (19)

A dry 100 mL round-bottomed flask equipped with a magnetic stir bar anda rubber septum was charged with1-{[1-((2E)-3-phenylprop-2-enoyloxy)-2-methylpropoxy]carbonylamino}cyclopropanecarboxylicacid (18) (0.62 g, 1.8 mmols) and 10% palladium on carbon in a 1: Imixture of ethylacetate and ethanol. The reaction was done at 1 atmpressure under a hydrogen balloon at ca. room temperature. After thereaction was complete, the solution was filtered through Celite and thesolvents removed in vacuo using a rotary evaporator. The dry, cruderesidue was dissolved in a small amount of a mixture of 60% (v/v)acetonitrile/water (ca. 10 mL), and the solution filtered through a 0.2μm nylon syringe filter. Final purification was achieved by mass-guidedpreparative HPLC. After lyophilization of the solvents, the titlecompound (19) was obtained as a yellow semisolid (70% yield). ¹H NMR(CDCl₃, 400 MHz): δ=7.33 (t, 2H), 7.20 (m, 3H), 6.61 (d, 1H), 6.05 (s,0.35H), 5.35 (s, 0.65H), 2.98 (t, 2H), 2.71 (m, 2H), 2.01 (m, 1H), 1.65(m, 2H), 1.36 (m, 2H), 0.98 (d, 6H). MS (ESI) m/z 371.92 (M+Na)⁺; 348.01(M−H)⁻.

Example 201-{[(2-Phenylacetyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic Acid(20)

Following the general procedure for the one pot synthesis, ACPC (1.02 g,9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) inanhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol).Subsequent reaction of the intermediate with 1-chloro-2-methylpropylchloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64mL, 19.7 mmol) and phenylacetic acid (2.6 g, 19.7 mmol) provided 0.560 g(14.4% yield) the title compound (20) as a yellow solid after aqueouswork-up and mass-guided preparative HPLC purification. M.p: 142.1-145.6°C. ¹H NMR (CDCl₃, 400 MHz): δ=7.33 (m, 5H), 6.81 (q, 1H), 5.31 (s, 1H),3.61 (s, 2H), 1.63 (m, 2H), 1.47 (d, 3H), 1.28 (m, 2H). MS (ESI) m/z330.08 (M+Na)⁺.

Example 211-{[(4-Methylphenylcarbonyloxy)ethoxy]carbonylamino}cyclopropanecarboxylicAcid (21)

Following the general procedure for the one pot synthesis, ACPC (1.02 g,9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) inanhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol).Subsequent reaction of the intermediate with 1-chloro-2-methylpropylchloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64mL, 19.7 mmol) and p-toluic acid (2.6 g, 19.7 mmol) provided 0.436 g(14.3% yield) the title compound (21) as a white solid after aqueouswork-up and mass-guided preparative HPLC purification. M.p: 177.7-182.5°C. ¹H NMR (CDCl₃, 400 MHz): δ=7.91 (d, 2H), 7.22 (m, 4H), 7.02 (q, 1H),5.38 (s, 1H), 2.43 (s, 3H), 1.63 (m, 5H) 1.36 (m, 2H). MS (ESI) m/z329.93 (M+H)⁺; 305.97 (M−H)⁻.

Example 221-[(Adamantanecarbonyloxyethoxy)carbonylamino]cyclopropanecarboxylicAcid (22)

Following the general procedure for the one pot synthesis, ACPC (1.02 g,9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) inanhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol).Subsequent reaction of the intermediate with 1-chloro-2-methylpropylchloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64mL, 19.7 mmol) and admantane carboxylic acid (3.5 g, 19.7 mmol) provided0.220 g (6.4% yield) of the title compound (22) as a white solid afteraqueous work-up and mass-guided preparative HPLC purification. ¹H NMR(CDCl₃, 400 MHz): δ=6.81 (q, 1H), 5.62 (s, 0.2H), 5.38 (s, 0.8H), 2.09(m, 4H), 1.93 (m, 6H), 1.72 (m, 6H), 1.61 (s, 2H), 1.52 (d, 3H), 1.37(br s, 2H). MS (ESI) m/z 374.01 (M+H)⁺, M−H=350.04 (M−H)⁻.

Example 231-{[2-Methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}SodiumCyclopropanoate (23)

A screw-capped 40 mL glass vial equipped with a magnetic stir bar wascharged with1-(1-isobutyryloxy-2-methyl-propoxycarbonylamino)-cyclopropanecarboxylicacid (2) (0.3 g, 1.04 mmol) in 4 mL of acetonitrile. An aqueous solutionof sodium bicarbonate (0.0873 g, 1.044 mmol) in 4 mL water was added tothe stirred solution and the mixture stirred for ca. 1 h at roomtemperature. The clear solution was frozen at −78° C. and the solutionlyophilized to provide 0.325 g (99.4% yield) of the title compound (23)as a transparent solid. ¹H NMR (D₂O, 400 MHz): δ=6.37 (d, 1H), 2.58 (m,1H), 1.98 (m, 1H), 1.26 (m, 2H), 1.02 (m, 6H), 0.92 (m, 2H), 0.88 (m,6H). MS (ESI) m/z 310.24 (M+H)⁺.

Example 24(2R)-2-{[(2,2-Dimethylpropanoyloxy)ethoxy]carbonylamino}-3-hydroxypropanoicAcid (24)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (504 mg, 4.8 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2,2-dimethylpropanoate (1.1 g,4.0 mmol) were reacted to provide 305 mg (28% yield) of the titlecompound (24) as a white powder after work-up and mass-guidedpreparative HPLC purification. ¹H NMR (CDCl₃, 400 MHz): δ=6.78 (m, 1H),6.40 (br s, 1H), 6.11 (t, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.93 (m, 1H),1.44 (2d, 3H), 1.20 (s, 9H). MS (ESI) m/z 278.05 (M+H)⁺; 295.06(M+NH₄)⁺; 300.04 (M+Na)⁺; 276.04 (M−H)⁻.

Example 25(2R)-3-Hydroxy-2-{[(2-methylphenVlcarbonyloxy)ethoxy]carbonylamino}propanoicAcid (25)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (252 mg, 2.4 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylbenzoate (642 mg, 2.0mmol) were reacted to provide 203 mg (33% yield) of the title compound(25) as a white powder after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CDCl₃, 400 MHz): δ=7.85 (br d, 1H), 7.39 (m, 1H),7.20 (m, 2H), 7.01 (m, 1H), 6.61 (br s, 1H), 6.08 (t, 1H), 4.40 (m, 1H),4.02 (m, 1H), 3.94 (m, 1H), 2.58 (s, 3H), 1.58 (2d, 3H). MS (ESI) m/z312.01 (M+H)⁺; 329.08 (M+NH₄)⁺; 334.06 (M+Na)⁺.

Example 26(2R)-3-Hydroxy-2-{[(3-methylbutanoyloxy)ethoxy]carbonylamino}propanoicAcid (26)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (252 mg, 2.4 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 3-methylbutanoate (574 mg, 2.0mmol) were reacted to provide 326 mg (59% yield) of the title compound(26) as a white powder after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CDCl₃, 400 MHz): δ=6.80 (m, 1H), 6.11 (m, 1H),5.78 (br s, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.94 (m, 1H), 2.01-2.24 (m,3H), 1.48 (2d, 3H), 0.99 (2d, 6H). MS (ESI) m/z 278.04 (M+H)⁺; 295.09(M+NH₄)⁺; 300.04 (M+Na)⁺; 276.10 (M−H)⁻.

Example 27(2R)-2-[(Cyclohexylcarbonyloxyethoxy)carbonylamino]-3-hydroxypropanoicAcid (27)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (252 mg, 2.4 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl cyclohexanecarboxylate (626 mg,2.0 mmol) were reacted to provide 350 mg (58% yield) of the titlecompound (27) as a white powder after work-up and mass-guidedpreparative HPLC purification. ¹H NMR (CDCl₃, 400 MHz): δ=6.79 (m, 1H),6.05 (t, 1H), 5.45 (br s, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.92 (m, 1H),2.30 (m, 1H), 1.09-1.95 (m, 13H). MS (ESI) m/z 321.13 (M+NH₄)⁺; 326.09(M+Na)⁺; 302.06 (M−H)⁻.

Example 28(2R)-3-Hydroxy-2-[(phenylcarbonyloxyethoxy)carbonylamino]propanoic Acid(28)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (252 mg, 2.4 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl benzoate (614 mg, 2.0 mmol)were reacted to provide 410 mg (69% yield) the title compound (28) as awhite powder after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CDCl₃, 400 MHz): δ=8.00 (m, 2H), 7.55 (m, 1H),7.40 (m, 2H), 7.01 (m, 1H), 6.59 (br s, 1H), 6.21 (m, 1H), 4.39 (m, 1H),4.02 (m, 1H), 3.86 (m, 1H), 1.60 (2d, 3H). MS (ESI) m/z 298.10 (M+H)⁺;315.11 (M+NH₄)⁺, 320.07 (M+Na)⁺.

Example 29(2R)-3-Hydroxy-2-{[(2-methylpropanoyloxy)ethoxy]carbonylamino}propanoicAcid (29)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (252 mg, 2.4 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylpropanoate (546 mg, 2.0mmol) were reacted to provide 212 mg (40% yield) of the title compound(29) as a white powder after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CDCl₃, 400 MHz): δ=6.79 (m, 1H), 6.03 (t, 0.2H),5.58 (br s, 1H), 4.41 (m, 1H), 4.05 (m, 1H), 3.94 (m, 1H), 2.57 (m, 1H),1.48 (2d, 3H), 1.19 (2d, 6H). MS (ESI) nm/z 281.11 (M+NH₄)⁺; 286.11(M+Na)⁺; 262.12 (M−H)⁻.

Example 30 (2R)-2-[(Butanoyloxyethoxy)carbonylamino]-3-hydroxypropanoicAcid (30)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (252 mg, 2.4 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl butanoate (546 mg, 2.0 mmol)were reacted to provide 255 mg (40% yield) the title compound (30) as awhite powder after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CDCl₃, 400 MHz): δ=6.80 (m, 1H), 6.09 (t, 1H),5.81 (br s, 1H), 4.41 (m, 1H), 4.07 (m, 1H), 3.92 (m, 1H), 2.31 (m, 2H),1.65 (m, 2H), 1.50 (d, 3H), 0.99 (m, 3H). MS (ESI) m/z 286.07 (M+Na)⁺;262.06 (M−H)⁻.

Example 31 (2R)-3-Hydroxy-2-[(pentanoyloxyethoxy)carbonylamino]propanoicAcid (31)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (504 mg, 4.8 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl pentanoate (1.1 g, 4.0 mmol)were reacted to provide 809 mg (73% yield) of the title compound (31) asa white powder after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CDCl₃, 400 MHz): δ=6.80 (m, 1H), 6.26 (br s, 1H),5.50 (br s, 1H), 4.40 (m, 1H), 4.02 (m, 1H), 3.85 (m, 1H), 2.36 (m, 2H),1.60 (m, 2H), 1.47 (d, 3H), 1.37 (m, 2H), 0.91 (t, 3H). MS (ESI) m/z295.19 (M+NH₄)⁺; 300.08 (M+Na)⁺; 272.12 (M−H)⁻.

Example 32(2R)-3-Hydroxy-2-{[(2-methylpropanoyloxy)methoxy]carbonylamino}propanoicAcid (32)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (161 mg, 1.5 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)methyl 2-methylpropanoate (330 mg,1.3 mmol) were reacted to provide 110 mg (35% yield) of the titlecompound (32) as a white powder after work-up and mass-guidedpreparative HPLC purification. ¹H NMR (CDCl₃, 400 MHz): δ=6.61 (br s,1H), 6.51 (d, 1H), 5.65 (m, 2H), 4.41 (m, 1H), 4.02 (m, 1H), 3.84 (m,1H), 2.59 (m, 1H), 1.09 (d, 6H). MS (ESI) m/z 250.15 (M+H)⁺; 267.17(M+NH₄)⁺; 272.13 (M+Na)⁺; 248.12 (M−H)⁻.

Example 33(2R)-3-Hydroxy-2-{[2-methyl-1-(2-ethylpropanoyloxy)propoxy]carbonylamino}propanoicAcid (33)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (252 mg, 2.4 mmol) and1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanoate(600 mg, 2.0 mmol) were reacted to provide 0.290 mg (50% yield) of thetitle compound (33) as a white powder after work-up and mass-guidedpreparative HPLC purification. ¹H NMR (CDCl₃, 400 MHz): δ=6.58 (2d, 1H),6.45 (br s, 1H), 6.50 (2d, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.90 (m,1H), 2.59 (m, 1H), 2.02 (m, 1H), 1.19 (m, 6H), 0.99 (d, 6H). MS (ESI)m/z 309.24 (M+NH₄)⁺; 314.22 (M+Na)⁺; 290.21 (M−H)⁻.

Example 342-[(1-Cyclohexylcarbonyloxy-2-methylpropoxy)carbonylamino]-3-hydroxypropanoicAcid (34)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (0.40 g, 3.80 mmol) and1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropylcyclohexanecarboxylate (1.0 g, 2.93 mmol) were reacted in theacetonitrile/water mixture to provide 0.091 g (10% yield) of the titlecompound (34) as a white wax after work-up and mass-guided preparativeHPLC purification. ¹H NMR (CDCl₃, 400 MHz): δ=6.58 (dd, 1H), 6.11 (dd,1H), 4.42-4.31 (m, 1H), 4.11-3.92 (br dd, 2H), 2.38 (m, 1H), 2.11 (m,1H), 1.97 (br d, 2H), 1.77 (br d, 2H), 1.6 (br d, 1H), 1.4 (q, 2H), 1.2(br m, 3H), 0.99 (dd, 6H). MS (ESI) m/z 354.22 (M+Na)⁺; 330.21 (M−H).

Example 353-Hydroxy-2-[(2-methyl-1-phenylcarbonyloxypropoxy)carbonylamino] (35)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (0.40 g, 3.8 mmol) and1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl benzoate (1 g, 2.98mmol) were reacted in the acetonitrile/water mixture to provide 0.121 g(13% yield) of the title compound (35) as a colorless, waxy materialafter work-up and mass-guided preparative HPLC purification. ¹H NMR(CDCl₃, 400 MHz): δ=8.01 (d, 2H), 7.4 (q, 1H), 7.43 (m, 2H), 6.8 (dd,1H), 5.99 (dd, 1H), 4.40 (m, 1H), 4.2-3.8 (m, 2H), 2.18 (m, 1H), 1.01(m, 6H). MS (ESI) m/z 348.15 (M+Na)⁺; 324.15 (M−H)⁻.

Example 36 (2R)-2-[(Heptanoyloxyethoxy)carbonylamino]-3-hydroxypropanoicAcid (36)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, D-serine (0.509 g, 4.8 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl heptanoate (1 g, 4.03 mmol)were reacted to provide 0.683 g (70% yield) of the title compound (36)as a colorless liquid after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CDCl₃, 400 MHz): δ=6.81 (q, 1H), 5.9 (t, 1H), 4.4(br s, 1H), 4.14-3.98 (m, 2H), 2.36 (t, 2H), 1.63 (t, 2H), 1.5 (d, 3H),1.3 (m, 6H), 0.85 (t, 3H). MS (ESI) m/z 327.97 (M+Na)⁺; 304.00 (M−H)⁻.

Example 372-{N-Methyl[2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}aceticAcid (37)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.108 g, 1.19 mmol) and1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanoate(0.3 g, 0.99 mmol) were reacted to provide 0.152 g (55% yield) of thetitle compound (37) as a colorless liquid after work-up and mass-guidedpreparative HPLC purification. ¹H NMR (CD₃OD, 400 MHz): δ=6.57 (dd, 1H),4.19 (m, 2H), 3.03 (2s, 3H), 2.6 (m, 1H), 2.01 (br m, 1H), 1.18 (m, 6H),1.0-0.98 (2m, 6H). MS (ESI) m/z 298.14 (M+Na)⁺, 274.13 (M−H)⁻.

Example 38 2-{N-Methyl[(2-methylpropanoyloxy)ethoxy]carbonylamino}aceticAcid (38)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.23 g, 2.63 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylpropanoate (0.6 g, 2.1mmol) were reacted to provide 0.459 g (85% yield) of the title compound(38) as a colorless liquid after work-up and mass-guided preparativeHPLC purification. ¹H NMR (CD₃OD, 400 MHz): δ=6.88 (q, 1H), 4.12 (m,2H), 2.9 (2s, 3H), 2.59 (m, 1H), 1.5-1.4 (2d, 3H), 1.1 (m, 6H). MS (ESI)m/z 270.06 (M+Na)⁺; 246.12 (M−H)⁻.

Example 392-{N-Methyl[(2-methylphenylcarbonyloxy)ethoxy]carbonylamino}acetic Acid(39)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.2 g, 2.24 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylbenzoate (0.6 g, 1.86mmol) were reacted to provide 0.293 g (53.1% yield) of the titlecompound (39) as a white wax after work-up and mass-guided preparativeHPLC purification. ¹H NMR (CD₃OD, 400 MHz): δ=7.81 (d, 1H), 7.40 (t,1H), 7.22 (d, 2H), 7.01 (q, 1H), 4.1 (m, 2H), 3.0 (2s, 3H), 2.58 (s,3H), 1.61-1.59 (2d, 3H). MS (ESI) m/z 318.07 (M+Na)⁺, 294.10 (M−H)⁻.

Example 40 2-[N-Methyl(phenylcarbonyloxyethoxy)carbonylamino]acetic Acid(40)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.104 g, 1.17 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl benzoate (0.3 g, 0.976 mmol)were reacted to provide 122 mg (44% yield) of the title compound (40) asa colorless semi-solid after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CD₃OD, 400 MHz): δ=8.01 (d, 2H), 7.61 (t, 1H),7.44 (t, 2H), 7.01 (q, 1H), 4.12 (m, 2H), 3.01 (2s, 3H), 1.62-1.58 (dd,3H). MS (ESI) m/z 304.05 (M+Na)⁺; 280.11 (M−H)⁻.

Example 412-{[(2,2-Dimethylpropanoyloxy)ethoxy]-N-methylcarbonylamino}acetic Acid(41)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.104 g, 1.17 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2,2-dimethylpropanoate (0.280g, 0.975 mmol) were reacted to provide 0.224 g (88% yield) of the titlecompound (41) as a colorless semi-solid after work-up and mass-guidedpreparative HPLC purification. ¹H NMR (CD₃OD, 400 MHz): δ=6.72 (q, 1H),4.08 (m, 2H), 3.02 (2s, 3H), 1.52-1.40 (dd, 3H), 1.19 (s, 9H). MS (ESI)m/z 284.08 (M+Na)⁺; 260.11 (M−H)⁻.

Example 42 2-[(Cyclohexylcarbonyloxyethoxy)-N-methylcarbonylamino]aceticAcid (42)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.104 g, 1.1 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl cyclohexanecarboxylate (0.292g, 0.93 mmol) were reacted to provide 0.213 g (79.7% yield) of the titlecompound (42) as a white waxy solid after work-up and mass-guidedpreparative HPLC purification. ¹H NMR (CD₃OD, 400 MHz): δ=6.75 (q, 1H),4.1 (m, 2H), 3.01 (2s, 3H), 2.3 (m, 1H), 1.90 (br m, 2H)), 1.75 (m, 2H),1.65, (m, 1H), 1.5-1.39 (2d, 5H), 1.4 (m, 3H). MS (ESI) m/z 310.19(M+Na)⁺, 289 (M−H)⁻.

Example 43 2-[N-Methyl(pentanoyloxyethoxy)carbonylamino]acetic Acid (43)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.104 g, 1.1 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl pentanoate (0.268 g, 0.93 mmol)were reacted to provide 0.130 g (53.3% yield) of the title compound (43)as a white powder after work-up and mass-guided preparative HPLCpurification. ¹H NMR (CD₃OD, 400 MHz): δ=6.79 (q, 1H), 4.12 (m, 2H), 3.0(2s, 2H), 2.36 (m, 2H), 1.62 (q, 2H), 1.56 (2d, 3H), 1.39 (q, 2H), 0.97(t, 3H). MS (ESI) m/z 284.09 (M+Na)⁺; 260.05 (M−H)⁻.

Example 44 2-[(Butanoyloxyethoxy)-N-methylcarbonylamino]acetic Acid (44)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.117 g, 1.3 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl butanoate (0.303 g, 1.09 mmol)were reacted to provide 0.147 g (53.6% yield) the title compound (44) asa colorless, sticky material after work-up and mass-guided preparativeHPLC purification. ¹H NMR (CD₃OD, 400 MHz): δ=6.78 (q, 1H), 4.12 (m,2H), 3.01 (2s, 3H), 2.33 (m, 2H), 1.62 (q, 2H), 1.51 (2d, 3H), 0.98 (t,3H). MS (ESI) m/z 270.08 (M+Na)⁺; 246.09 (M−H)⁻.

Example 45 2-{N-Methyl[(3-methylbutanoyloxy)ethoxy]carbonylamino}aceticAcid (45)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.104 g, 1.1 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl 3-methylbutanoate (0.28 g, 0.97mmol) were reacted to provide 0.070 g (27.5% yield) of the titlecompound (45) as a colorless, waxy material after work-up andmass-guided preparative HPLC purification. ¹H NMR (CD₃OD, 400 MHz):δ=6.78 (q, 1H), 4.12 (m, 2H), 2.99 (2s, 3H), 2.23 (m, 2H), 2.12 (m, 1H),1.52 (2d, 3H), 0.99 (t, 3H). MS (ESI) m/z 284.08 (M+Na)⁺, 260.13 (M−H)⁻.

Example 462-{N-Methyl[(2-methylpropanoyloxy)methoxy]carbonylamino}acetic Acid (46)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.123 g, 1.3 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)methyl 2-methylpropanoate (0.300 g,1.1 mmol) were reacted to provide 0.138 g (5.1.3% yield) of the titlecompound (46) as a colorless semi-solid material after work-up andmass-guided preparative HPLC purification. ¹H NMR (CD₃OD, 400 MHz):δ=5.78 (d, 2H), 4.12 (d, 3H), 3.02 (d, 3H), 2.62 (m, 1H), 1.2 (t, 6H).MS (ESI) m/z 256.05 (M+Na)⁺.

Example 472-[(1-Cyclohexylcarbonyloxy-2-methylpropoxy)-N-methylcarbonylamino]aceticAcid (47)

Following the general procedure for the synthesis of acyloxycarbamates,sarcosine (0.31 g, 3.50 mmol) and1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropylcyclohexanecarboxylate (1.0 g, 2.92 mmol) were reacted in anacetonitrile/water mixture (20 mL) to provide 0.146 g (16% yield) of thetitle compound (47) as a white, waxy material after work-up andmass-guided preparative HPLC purification. ¹H NMR (CDCl₃, 400 MHz):δ=6.60 (t, 1H), 4.20-3.82 (m, 2H), 3.01 (d, 3H), 2.39 (m, 1H), 2.15 (m,1H), 1.98 (br d, 2H), 1.80 (br d, 2H), 1.71 (br s, 1H), 1.53 (m, 2H),1.32 (m, 3H), 1.01 (2d, 6H). MS (ESI) 1 m/z 337.99 (M+Na)⁺; 314.02(M−H)⁻.

Example 482-[N-Methyl(2-methyl-1-phenylcarbonyloxypropoxy)carbonylamino]aceticAcid (48)

Following the general procedure for the synthesis ofacyloxyalkylcarbamates, sarcosine (0.345 g, 3.8 mmols) and1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl benzoate (1 g, 2.98mmol) were reacted in an acetonitrile/water mixture (20 mL) to provide0.364 g (39.5% yield) of the title compound (48) as a colorless, waxymaterial after work-up and mass-guided preparative HPLC purification. ¹HNMR (CDCl₃, 400 MHz): δ=8.05 (t, 2H), 7.59 (t, 1H), 7.43 (t, 2H), 6.84(m, 1H), 4.21-3.88 (br m, 2H), 3.0 (d, 3H), 2.25 (m, 1H), 1.15 (dd, 6H).MS (ESI) m/z 332.20 (M+Na)⁺; 308.21 (M−H)⁻.

Example 49 2-[(Heptanoyloxyethoxy)-N-methylcarbonylamino]acetic Acid(49)

Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.430 g, 4.8 mmol) and(2,5-dioxoazolidinyloxycarbonyloxy)ethyl heptanoate (1 g, 4.02 mmol)were reacted together to provide 0.135 g (14.7% yield) of the titlecompound (49) as a colorless liquid after work-up and mass-guidedpreparative HPLC purification. ¹H NMR (CDCl₃, 400 MHz): δ=6.80 (q, 1H),4.21-3.88 (m, 1H), 3.98 (m, 1H), 3.01 (s, 3H), 2.31 (m, 2H), 1.64 (m,2H), 1.5 (2d, 3H), 1.32 (m, 6H), 0.98 (t, 3H). MS (ESI) m/z 312.13(M+Na)⁺; 288.15 (M−H)⁻.

Example 502-[N-Methyl(phenylphenylcarbonyloxymethoxy)carbonylamino]acetic Acid(50) Step A: Chlorophenylchloroformate

A solution of benzaldehyde (5 g, 47.1 mmol), and pyridine (0.53 mL, 4.71mmol) in CCl₄ was stirred under a nitrogen atmosphere at −20° C.Trichloromethyl carbonate (6.90 g, 23.5 mmol) was added in portions for5 min such that the reaction temperature was maintained at −20° C. Theresulting viscous solution was warmed at ca. room temperature over 90min followed by heating to 40° C. for one hour. The reaction mixture wascooled and stirred overnight at ca. room temperature. Filtration ofpyridinum salts followed by removal of solvent in vacuo gave crudechlorophenylchloroformate, which was used without further purification.

Step B: 2-[N-methyl(phenylphenylcarbonyloxymethoxy)carbonylamino]aceticAcid

Following the general procedure for the one pot synthesis, sarcosine(1.0 g, 11.2 mmol) was reacted with chlorotrimethylsilane (2.8 mL, 22.4mmol) in anhydrous chloroform (25 mL) in the presence of DIEA (4.1 mL,22.4 mmol). Subsequent reaction of the intermediate with1-chloro-2-methylpropyl chloroformate (4.59 g, 22.4 mmol) followed by amixture of DIEA (4.1 mL, 22.4 mmol) and benzoic acid (2.8 g, 22.4 mmol)provided 0.622 g (16.3% yield) of the title compound (50) as abuff-colored solid after aqueous work-up and mass-guided preparativeHPLC purification. ¹H NMR (CD₃OD, 400 MHz): δ=8.13 (d, 2H), 7.81 (d,1H), 7.61 (m, 3H), 7.57 (m, 5H), 4.10 (br m, 2H), 3.01 (2s, 3H). MS(ESI) m/z 366.14 (M+Na)⁺.

Example 51 Methods for Determination of Enzymatic Cleavage of ProdrugsIn Vitro

For a prodrug, it may be desirable that the prodrug remains intact(i.e., uncleaved) while in the systemic circulation and be cleaved(i.e., to release the parent drug) in the target tissue. Alternatively,it may be desirable that the prodrug remains intact (i.e., uncleaved)while in the gastrointestinal tract and be cleaved (i.e., to release theparent drug) after being absorbed or taken up from the gastrointestinallumen, e.g., in either the enterocytes lining the gastrointestinal lumenor in the blood. A useful level of stability may at least in part bedetermined by the mechanism and pharmacokinetics of the prodrug. Auseful level of liability may at least in part also be determined by thepharmacokinetics of the prodrug and parent drug in the systemiccirculation and/or in the gastrointestinal tract, if orallyadministered. In general, prodrugs that are more stable in pancreatin orcolonic wash assay and are more labile in a rat plasma, human plasma,rat liver S9, and/or human liver S9 preparations may be useful as anorally administered prodrug. In general, prodrugs that are more stablein rat plasma, human plasma, rat liver S9, and/or human liver S9preparations and which are more labile in cell homogenate preparations,such Caco-2 S9 preparations, may be useful as systemically administeredprodrugs and/or may be more effective in delivering a prodrug to atarget tissue. In general, prodrugs that are more stable in different pHphysiological buffers (e.g., ranging from about pH 6.0 to pH 8.5) may bemore useful as prodrugs. In general, prodrugs that are more labile incell homogenate preparations, such Caco-2 S9 preparations, may beintracellularly cleaved to release the parent drug to a target tissue.The results of tests, such as those described in this example, fordetermining the enzymatic or chemical cleavage of prodrugs in vitro maybe used to select prodrugs for in vivo testing.

The stabilities of prodrugs may be evaluated in one or more in vitrosystems using a variety of preparations following methods known in theart. Tissues and preparations are obtained from commercial sources(e.g., Pel-Freez Biologicals, Rogers, Ark., or GenTest Corporation,Woburn, Mass.). Experimental conditions useful for the in vitro studiesare described in Table 1. The prodrug is added to each preparation intriplicate.

For preparations that contain alkaline phosphatases, the prodrug istested in the presence and absence of a phosphatase inhibitor cocktail(Sigma). Samples are incubated at 37° C. for times ranging from 30minutes to 24 hours. At each time point, samples are quenched with 50%ethanol. Baseline concentrations of the prodrug are determined by addingthe compound directly to the 50% ethanol/preparation mixture (t=0).Samples are centrifuged at 14,000 rpm for 15 minutes, and concentrationsof intact prodrug and released parent drug are determined usingLC/MS/MS. This stability of prodrugs towards specific enzymes (e.g.,peptidases, etc.) is also assessed in vitro by incubation with thepurified enzyme.

Pancreatin stability studies are conducted by incubating the prodrug (5μM) with 1% (w/v) pancreatin (Sigma, P-1625, from porcine pancreas) in0.025 M Tris buffer containing 0.5 M NaCl (pH 7.5) at 37° C. Thereaction is stopped by addition of 3 volumes of 50% ethanol. Aftercentrifugation at 14,000 rpm for 15 min, the supernatant is removed andanalyzed by LC/MS/MS.

To determine stability in Caco-2 homogenate S9, Caco-2 cells are grownfor 21 days prior to harvesting. Culture medium is removed and cellmonolayers are rinsed and scraped off into ice cold 10 mM sodiumphosphate/0.15 M potassium chloride, pH 7.4. Cells are lysed bysonication at 4° C. using a probe sonicator. Lysed cells are thentransferred into 1.5 mL centrifuge vials and centrifuged at 9,000 g for20 min at 4° C. The resulting supernatant (Caco-2 cell homogenate S9fraction) is aliquoted into 0.5 mL vials and stored at −80° C. untilused.

For stability studies, prodrug (5 μM) is incubated in Caco-2 homogenateS9 fraction (0.5 mg/mL in 0.1M Tris buffer, pH 7.4) at 37° C. Triplicatesamples are quenched at each time point with 50% ethanol. The initial(t=0) concentration of prodrug is determined by adding 5 μM prodrugdirectly to a 50% ethanol/Caco-2 homogenate mixture. Samples aresubjected to LC/MS/MS analysis to determine concentrations of theprodrug and the parent drug.

To determine prodrug stability in rat plasma, the prodrug (5 μM) isincubated in undiluted rat plasma. Triplicate samples are quenched ateach time point with 50% ethanol. The initial (t=0) concentration ofprodrug is determined by adding 5 μM prodrug directly to a 50%ethanol/rat plasma mixture. Samples are subjected to LC/MS/MS analysisto determine concentrations of prodrug and parent drug.

For rat S9 stability studies, prodrug (5 μM) is incubated in rat liverS9 homogenate (0.5 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, 1mM NADPH) at 37° C. Triplicate samples are quenched at each time pointwith 50% ethanol. The initial (t=0) concentration of prodrug isdetermined by adding 5 μM prodrug directly to a 50% ethanol/S9homogenate mixture. Samples are subjected to LC/MS/MS analysis todetermine concentrations of prodrug and parent drug.

Three buffers are used to determine the chemical stability of prodrug:(1) 0.1M potassium phosphate, 0.5 M NaCl, pH 2.0, (2) 0.1M Tris-HCl,0.5M NaCl, pH 7.4, and (3) 0.1 M Tris-HCl, 0.5 M NaCl, pH 8.0. Theprodrug (5 μM) is added to each buffer in triplicate. Samples arequenched at each time point with 50% ethanol. The initial (t=0)concentration of prodrug is determined by adding 5 μM prodrug directlyto a 50% ethanol/pH Buffer mixture. Samples are subjected to LC/MS/MSanalysis to determine concentrations of prodrug and parent drug.

TABLE 1 Standard Conditions for Prodrug In Vitro Metabolism StudiesProdrug Preparation Concentration Cofactors Rat Plasma 2.0 μM None HumanPlasma 2.0 μM None Rat Liver S9 2.0 μM NADPH* (0.5 mg/mL) Human Liver S92.0 μM NADPH* (0.5 mg/mL) Human Intestine S9 2.0 μM NADPH* (0.5 mg/mL)Caco-2 Homogenate 5.0 μM None Pancreatin 5.0 μM None *NADPH generatingsystem, e.g., 1.3 mM NADP⁺, 3.3 mM glucose-6-phosphate, 0.4 U/mLglucose-6-phosphate dehydrogenase, 3.3 mM magnesium chloride, and 0.95mg/mL potassium phosphate, pH 7.4.

Example 52 In Vitro Determination of Caco-2 Cellular Permeability ofProdrugs

The passive permeability of a prodrug provided by the present disclosuremay be assessed in vitro using standard methods well known in the art(see, e.g., Stewart, et al., Pharm. Res., 1995, 12, 693). For example,passive permeability may be evaluated by examining the flux of a prodrugacross a cultured polarized cell monolayer (e.g., Caco-2 cells). Caco-2cells obtained from continuous culture (passage less than 28) are seededat high density onto Transwell polycarbonate filters. Cells aremaintained with DMEM/10% fetal calf serum+0.1 mM nonessential aminoacids +2 mM L-Gln, 5% CO₂/95% O₂, 37° C. until the day of theexperiment. Permeability studies are conducted at pH 6.5 apically (in 50mM MES buffer containing 1 mM CaCl₂, 1 mM MgCl₂, 150 mM NaCl, 3 mM KCl,1 mM NaH₂PO₄, 5 mM glucose) and pH 7.4 basolaterally (in Hanks' balancedsalt solution containing 10 mM HEPES) in the presence of efflux pumpinhibitors (250 μM MK-571, 250 μM verapamil, 1 mM ofloxacin). Insertsare placed in 12 or 24 well plates containing buffer and incubated for30 min at 37° C. The prodrug (200 μM) is added to the apical orbasolateral compartment (donor) and concentrations of the prodrug and/orreleased parent drug in the opposite compartment (receiver) aredetermined at intervals over 1 hour using LC/MS/MS. Values of apparentpermeability (P_(app)) are calculated using the equation:

P _(app) =V _(r)(dC/dt)/(AC _(o))

where V_(r) is the volume of the receiver compartment in mL; dC/dt isthe total flux of prodrug and parent drug (μM/s), determined from theslope of the plot of concentration in the receiver compartment versustime; C_(o) is the initial concentration of prodrug in μM; and A is thesurface area of the membrane in cm². Prodrugs with significanttranscellular permeability generally demonstrate a value of P_(app) of≧1×10⁻⁶ cm/s, for example, a value of P_(app) of ≧1×10⁻⁵ cm/s, and avalue of P_(app) of ≧5×10⁻⁵ cm/s.

Example 53 Bioavailability of α-Amino Acid Prodrugs and MetabolitesThereof Following Intracolonic Administration in Rats and Monkeys

Rats are obtained commercially and were pre-cannulated in the both theascending colon and the jugular vein. Animals were conscious at the timeof the experiment. All animals were fasted overnight and until 4 hoursafter dosing of an α-amino acid prodrug. An α-amino acid or thecorresponding prodrug was administered as a solution (in water) directlyinto the colon via the cannula at a dose equivalent to about 75 mg orother appropriate dose of an α-amino acid per kg body weight. Bloodsamples (0.3 mL) were obtained from the jugular cannula at intervalsover 8 hours and were quenched immediately by addition of sodiummetabisulfite to prevent oxidation of the α-amino acid. Blood was thenfurther quenched with methanol/perchloric acid to prevent hydrolysis ofthe prodrug. Blood samples were analyzed as described.

For studies using monkeys, test compounds were administered byintracolonic bolus injection to groups of four adult male Cynomologous(Macaca fascicularis) monkeys (weight approx 3 kg) as solutions in wateror sodium phosphate buffer, pH 7.4, at a dose of 20 mg-equivalents of1-aminocyclopropanecarboxylic acid per kg body weight. Animals werefasted overnight before the study and for 4 hours post-dosing. Bloodsamples (1.0 mL) were obtained via the femoral vein at intervals over 24hours after oral dosing. Blood was quenched immediately using methanoland then frozen at −80° C. until analyzed. Test compounds wereadministered in the monkeys with a minimum of 7-day wash out periodbetween dosing sessions.

300 μL of methanol was added to 1.5 mL tubes. Rat or monkey blood (100μL) was collected at different times into the tubes and vortexed to mix.90 μL of blood was quenched with 300 μL methanol. 10 μL of a standardstock solution containing an α-amino acid (0.04, 0.2, 1, 5, 25, and 100μg/mL) and 20 μL of p-chlorophenylalanine eas added to 90 μL of blood tomake up a final calibration standard (0.004, 0.02, 0.1, 0.5, 2.5, and 10μg/mL). Samples were vortexed and centrifuged at 3400 rpm for 20 min.The supernatant was analyzed by LC/MS/MS.

An API 4000 LC/MS/MS spectrometer equipped with Agilent 1100 binarypumps and a CTC HTS-PAL autosampler and an Agilent Zorbax EclipseXBD-C8, 4.6×150 mm, 3.5 μM column was used for the analysis. The mobilephase was 0.02% heptafluorobutyric acid in water (A) and 0.02%heptafluorobutyric acid in acetonitrile (B). The flow rate was 1.0mL/min. The gradient condition was: 5% B for 2 min, then to 10% B for 1min. Then the mobile phase was returned to 5% B for 1.1 min. ATurboIonSpray source was used in the API 4000. The analysis was done ineither negative ion mode or positive ion mode as appropriate and the MRMtransition for each analyte was optimized using a standard solution. 20μL of the samples were injected. Non-compartmental analysis wasperformed using WinNonlin software (v.3.1 Professional Version,Pharsight Corporation, Mountain View, Calif.) on individual animalprofiles. Summary statistics on major parameter estimates was performedfor C_(max) (peak observed concentration following dosing), T_(max)(time to maximum concentration is the time at which the peakconcentration was observed), AUC_((0-i)) (area under the plasmaconcentration-time curve from time zero to last collection time,estimated using the log-linear trapezoidal method), AUC_((0-δ)), (areaunder the plasma concentration time curve from time zero to infinity,estimated using the log-linear trapezoidal method to the last collectiontime with extrapolation to infinity), and t_(1/2,z) (terminalhalf-life).

Prodrugs that provide a bioavailability of the corresponding α-aminoacid that is greater than the bioavailability provided by an equimolardose of the α-amino acid administered to a patient by the same route(e.g., oral administration) may be useful as therapeutic agents, andmore particularly, as sustained release therapeutic agents.

The oral or intracolonic bioavailability (F) of an α-amino acid wasdetermined by comparing the area under the α-amino acid concentrationvs. time curve (AUC) following oral or intracolonic administration ofα-amino acid or prodrug thereof with the AUC of the α-amino acidconcentration vs. time curve following intravenous administration of theα-amino acid on a dose normalized basis (e.g., % F_(ic)=AUC (followingintracolonic administration of an α-amino acid prodrug)/AUC (followingintravenous administration of an equivalent dose of the correspondingα-amino acid)). An AUC_(inf) of 85.9 μg·hr/mL for the intravenouslyadministered α-amino acid, 1-aminocyclopropanecarboxylic acid (dosed at20 mg-eq/kg) was used for the calculations of the bioavailability of1-aminocyclopropanecarboxylic acid released from the correspondingprodrugs post absorption in rats. Compounds 2, 3, 4, 11, 12, 16, 18, and23 showed substantial colonic bioavailability of1-aminocyclopropanecarboxylic acid in rats. In monkeys, following,colonic administration of α-amino acid prodrug 2, the bioavailability of1-aminocyclopropanecarboxylic acid was determined to be about 4-foldgreater than after colonic administration of1-aminocyclopropanecarboxylic acid itself (at 20 mg-eq/kg).

Example 54 PCP-Induced Hyperactivity Animal Model of Schizophrenia

Male C57Bl/6J mice from Jackson Laboratories (Bar Harbor, Me.) are used.Mice are received at 6-weeks of age. Upon receipt, mice are assignedunique identification numbers (tail marked) and are group housed with 4mice/cage in OPTI mouse ventilated cages. All animals remain housed ingroups of four during the study. All mice are acclimated to the colonyroom for at least two weeks prior to testing and are subsequently testedat an average age of 8 weeks of age. During the period of acclimation,mice and rats are examined on a regular basis, handled, and weighed toassure adequate health and suitability. Animals are maintained on a12/12 light/dark cycle. The room temperature is maintained between 20°C. and 23° C. with a relative humidity maintained between 30% and 70%.Chow and water are provided ad libitum for the duration of the study. Ineach test, animals are randomly assigned across treatment groups. Allanimals are euthanized at the end of the study.

Test compounds are prepared and administered according to the followingprocedures. An α-amino acid prodrug is dissolved in sterile injectablewater and administered i.p. at a dose volume of 10 mL/kg at 60 min priorto PCP injection. The amount of α-amino acid prodrug administered canrange, for example, from 0.01 mg/kg to 100 mg/kg. As a positive control,clozapine (1 mg/kg) is dissolved in 10% DMSO and administered i.p. at adose volume of 10 mL/kg at 30 min prior to PCP injection. PCP (5 mg/kg)is dissolved in sterile injectable water and administered i.p. at a dosevolume of 10 mL/kg.

The Open Field (OF) test is used to assess both anxiety and locomotorbehavior. The open field chambers are Plexiglas square chambers(27.3×27.3×20.3 cm; Med Associates Inc., St Albans, Vt.) surrounded byinfrared photobeams (16×16×16) to measure horizontal and verticalactivity. The analysis is configured to divide the open field into acenter and periphery zone. Distance traveled is measured from horizontalbeam breaks as a mouse moves, and rearing activity is measured fromvertical beam breaks.

Mice are acclimated to the activity experimental room for at least 1 hrto prior to testing. Eight animals are tested in each run. Mice areinjected with water or α-amino acid prodrug, placed in holding cages for30 min, and then in the OF chamber for 30 min, removed from the OFchamber and injected with either water or PCP and returned to the OFchambers for a 60-minute session. A different group of mice are injectedwith either 10% DMSO or clozapine and placed in the OF chamber for 30min, removed from the OF chamber and injected with PCP (5 mg/kg), andreturned to the OF chambers for a 60-minute session.

Data is analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to PCP injection.PCP-induced activity is measured during the 60 min following PCPinjection. Statistical outliers that fall above or below 2 standarddeviations from the mean are removed from the final analysis. An effectis considered significant if p<0.05.

Example 55 Auditory Startle and Prepulse Inhibition of Startle (PPI)Animal Model of Schizophrenia

Young, adult male C57Bl/6J mice from Jackson Laboratories (Bar Harbor,Me.) are used in this study. Mice are received at 6-weeks of age. Uponreceipt, mice are assigned unique identification numbers (tail marked)and are group housed in standard mouse cages. All animals remain housedin groups of four during the study. All mice are acclimated to thecolony room for at least two weeks prior to testing and are subsequentlytested at an average age of 8-9 weeks of age. During the period ofacclimation, mice are examined on a regular basis, handled, and weighedto assure adequate health and suitability. Mice are maintained on a 12h/12 h light/dark cycle with the light on at 7:00 a.m. The roomtemperature is maintained between 20° C. and 23° C. with a relativehumidity maintained between 30% and 70%. Feed and water are provided adlibitum during the study. For testing, animals are randomly assignedacross treatment groups and balanced by PPI chamber.

Test compounds are prepared and administered according to the followingprocedures. An α-amino acid prodrug is dissolved in sterile injectablewater and administered i.p. at a dose volume of 10 mL/kg at 60 min priorto testing. The amount of α-amino acid prodrug administered can range,for example, from 0.01 mg/kg to 100 mg/kg. Haloperidol (1 mg/kg) isdissolved in 10% DMSO and administered i.p. 30 minutes prior to testingthe normal mouse-PPI portion of the study. As a positive control,clozapine (3 mg/kg) is dissolved in 1% Tween and administered i.p. 60min prior to testing the PCP-PPI portion of the study. PCP (8 mg/kg) isdissolved in sterile injectable water and administered 30 minutes priorto testing. All compounds are delivered at a dose volume of 10 mL/kg.

Acoustic startle measures an unconditioned reflex response to externalauditory stimulation. PPI consisting of an inhibited startle response(reduction in amplitude) to an auditory stimulation following thepresentation of a weak auditory stimulus or prepulse, has been used as atool for the assessment of deficiencies in sensory-motor gating, such asthose seen in schizophrenia. Mice are placed in the PPI chamber (MedAssociates) for a 5 min session of white noise (70 dB) habituation. Atest session begins immediately after the 5 min acclimation period. Thesession starts with a habituation block of 6 presentations of thestartle stimulus alone, followed by 10 PPI blocks of 6 different typesof trials. Trial types are: null (no stimuli), startle (120 dB), startleplus prepulse (4, 8 and 12 dB over background noise i.e., 74, 78 or 82dB) and prepulse alone (82 dB). Trial types are presented at randomwithin each block. Each trial begins with a 50 ms null period duringwhich baseline movements are recorded. There is a subsequent 20 msperiod during which prepulse stimuli are presented and responses to theprepulse measured. Following a 100 ms pause, the startle stimuli arepresented for 40 ms and responses are recorded for 100 ms from startleonset. Responses are sampled every ms. The inter-trial interval isvariable with an average of 15 s (range from 10 to 20 s). In startlealone trials the basic auditory startle is measured and in prepulse plusstartle trials the amount of inhibition of the normal startle isdetermined and expressed as a percentage of the basic startle response(from startle alone trials), excluding the startle response of the firsthabituation block.

For the normal mouse-PPI portion of the study, C57BL/6J mice are treatedwith vehicle, haloperidol or α-amino acid and placed back in theirholding cages. Thirty min following injection of vehicle or haloperidoland 60 min following injection of vehicle or α-amino acid, normalmouse-PPI testing commenced.

For the PCP-PPI portion of the study, C57BL/6J mice are treated withvehicle, clozapine, or α-amino acid prodrug and returned to theirholding cages. Thirty min later, all treatment groups are injected withvehicle or PCP. Thirty min following vehicle or PCP injection, PPItesting commences.

Mice are returned to holding cages and sacrificed immediately followingtesting.

Data is analyzed by analysis of variance (ANOVA) followed by post-hocanalysis when appropriate. An effect is considered significant ifp<0.05. For the PPI analysis, all mice that had a startle response below100 are removed from the analysis.

Example 56 Animal Model for Assessing Therapeutic Efficacy of α-AminoAcid Prodrugs for Treating Anxiety

A method for assessing the effects of test compounds on anxietydescribed by Pellow and File, Pharmacol Biochem Behav 1986, 24, 524-529,i.e., the elevated plus-maze test, is used. A plus-maze is consists oftwo open arms (50×10 cm) and two closed arms (50×10×40 cm). The armsextend from a central platform (10×10 cm) and are raised 50 cm. Eachmouse is placed at the center of the maze facing a closed arm and isallowed to explore the maze for 5 min. The time spent in the open armsand the time spent in the closed arms is monitored, and the percent oftime spent in the open arms determined. Increased time spent in the openarms indicates an anxiolytic effect for the test condition. A test thatmeasures spontaneous locomotor activity such as measurement in anactivity cage can be used to determine whether the test compound alsoaffects locomotor activity. It is desirable that a compound exhibitingan anxiolytic effect not decrease locomotor activity.

Example 57 Animal Models of Depression Forced Swim Test in Rats

Male Wistar rats weighting 230-270 g are acclimated to the colony roomfor a minimum of I week, handled daily for at least 4 days andhabituated to saline injections for 2 days before the experiments.

Two glass cylinders (20 cm dia×40 cm height) are separated by blackopaque partitions and filled with water at about 24° C. to a depth of 30cm. At this depth a rat cannot stand on the cylinder bottom. The waterlevel is 10 cm from the top. Water is changed before each animal isplaced into the water tank. An experimental session consists of twotrials. During the conditioning trial, rats are gently placed into thecylinders for 15 min. After the trail, rats are dried and placed into awarm cage with the paper towels for 10-15 min before being returned totheir home cages. Twenty-four hours later, for the test trail, animalsare placed again into the cylinders for a 5-min test session. Tests arevideo taped for subsequent quantitative behavioral analysis. Thefrequency and/or total duration are calculated for each of the followingcategories: passive/immobile behavior (floating is scored when an animalremains in the water with all four limbs motionless, except foroccasional alternate movements of paws and tail necessary to preventsinking and to keep head/nose above the water); active/mobile behaviors(swimming characterized by rigorous movements with all four legs;paddling characterized by floating with rhythmical simultaneous kicksand occasional pushes off the wall to give speed and direction to thedrift), including escape-oriented behaviors (climbing characterized byintense movements with all four limbs, with the two forepaws breakingthe surface of the water and being directed against the walls of thecylinder; diving characterized by movements towards the bottom of thecylinder with the head of the rat below its hind limbs), andself-directed behaviors (headshakes, vigorous headshakes to get wateroff the snout and eyes; wiping, rubbing water away form the snout). Inaddition, at the end of each test trial, fecal boli are counted. A testcompound, control, or positive control (e.g., imipramine) isadministered prior to the test.

Tail Szispension Test in Mice

Mice are housed in standard laboratory cages and acclimated. Mice aremoved from the housing room to the testing area in their home cages andallowed to adapt to the new environment for at least 1 h before testing.Immobility is induced by tail suspension according to the procedure ofSteru et al., Psychopharmacology 1985, 85, 367-370. Mice are hungindividually on a paper adhesive tape, 65 cm above a tabletop. Tape isplaced approximately 1 cm from the tip of the tail. Animals are allowedto hang for 6 min and the duration of immobility is recorded. Mice areconsidered immobile only when hanging passively and completelymotionless. Mice from these experiments are used one week later inlocomotor activity studies. A test compound, control, or positivecontrol (e.g., imipramine) is administered prior to the test.

Locomotor Activity

The spontaneous locomotor activity of rats is measured in photoresistoractometers (40×40×25 cm, two light sources, two photoresistors), wherethe animals are placed after administration of a test compound. Thenumber of crossings of light beams is measured during the first 30 minof an experimental session. The first measurement is performed 5 minafter placing an animal in the actometer.

Example 58 Animal Model for Assessing Therapeutic Efficacy of α-AminoAcid Prodrugs for Treating Spasticity

The mutant spastic mouse is a homozygous mouse that carries an autosomalrecessive trait of genetic spasticity characterized by a deficit ofglycine receptors throughout the central nervous system (Chai et al.,Proc. Soc. Exptl. Biol. Med. 1962, 109, 491). The mouse is normal atbirth and subsequently develops a coarse tremor, abnormal gait, skeletalmuscle rigidity, and abnormal righting reflexes at two to three weeks ofage. Assessment of spasticity in the mutant spastic mouse can beperformed using electrophysiological measurements or by measuring therighting reflex (any righting reflex over one second is consideredabnormal), tremor (holding mice by their tails and subjectively ratingtremor), and flexibility.

Models of acute spasticity including the acute decerebrate rat, theacute or chronic spinally transected rat, and the chronically spinalcord-lesioned rat (see e.g., Wright and Rang, Clin Orthop Relat Res1990, 253, 12-19; Shimizu et al., J Pharmacol Sci 2004, 96, 444-449; andLi et al., J Neurophysiol 2004, 92, 2694-2703). The acute models,although valuable in elucidating the mechanisms involved in thedevelopment of spasticity, have come under criticism due to the factthat they are acute. The animals usually die or have total recovery fromspasticity. The spasticity develops immediately upon intervention,unlike the spasticity that evolves in the human condition of spasticity,which most often initially manifests itself as a flaccid paralysis. Onlyafter weeks and months does spasticity develop in humans. Some of themore chronic-lesioned or spinally transected models of spasticity dopostoperatively show flaccid paralysis. At approximately four weekspost-lesion/transection, the flaccidity changes to spasticity ofvariable severity. Although all of these models have their ownparticular disadvantages and lack of true representation of the humanspastic condition, they are shown useful in developing treatments forspasticity in humans. Many of these models have also made use ofdifferent species, such as cats, dogs, and primates. Baclofen, diazepam,and tizanidine, effective antispastic agents in humans, are effective ondifferent parameters of electrophysiologic assessment of muscle tone inthese models.

The Irwin Test is used to detect physiological, behavioral, and toxiceffects of a test substance, and indicates a range of dosages that canbe used for later experiments (Irwin, Psychopharmacologia 1968, 13,222-57). Typically, rats (three per group) are administered the testsubstance and are then observed in comparison with a control group givenvehicle. Behavioral modifications, symptoms of neurotoxicity, pupildiameter, and rectal temperature are recorded according to astandardized observation grid derived from that of Irwin. The gridcontains the following items: mortality, sedation, excitation,aggressiveness, Straub tail; writhes, convulsions, tremor, exopthalmos,salivation, lacrimation, piloerection, defecation, fear, traction,reactivity to touch, loss of righting reflexes, sleep, motorincoordination, muscle tone, stereotypes, head-weaving, catalepsy,grasping, ptosis, respiration, corneal reflex, analgesia, abnormal gait,forepaw treading, loss of balance, head twitches, rectal temperature,and pupil diameter. Observations are performed at 15, 30, 60, 120, and180 minutes following administration of a test compound, and also 24hours later.

In the Rotarod Test (Dunham et al., J. Am. Pharm. Assoc. 1957, 46,208-09) rats or mice are placed on a rod rotating at a speed of eightturns per minute. The number of animals that drop from the rod beforethree minutes is counted and the drop-off times are recorded (maximum:180 sec). Diazepam, a benzodiazepine, can be administered at 8 mg/kg,i.p., as a reference substance.

Example 59 Animal Models for Assessing Therapeutic Efficacy of α-AminoAcid Prodrugs for Treating Parkinson's Disease MPTP InducedNeurotoxicity

MPTP, or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a neurotoxinthat produces a Parkinsonian syndrome in both man and experimentalanimals. Studies of the mechanism of MPTP neurotoxicity show that itinvolves the generation of a major metabolite, MPP⁺, formed by theactivity of monoamine oxidase on MPTP. Inhibitors of monoamine oxidaseblock the neurotoxicity of MPTP in both mice and primates. Thespecificity of the neurotoxic effects of MPP⁺ for dopaminergic neuronsappears to be due to the uptake of MPP⁺ by the synaptic dopaminetransporter. Blockers of this transporter prevent MPP⁺ neurotoxicity.MPP⁺ has been shown to be a relatively specific inhibitor ofmitochondrial complex I activity, binding to complex I at the retenonebinding site and impairing oxidative phosphorylation. In vivo studieshave shown that MPTP can deplete striatal ATP concentrations in mice. Ithas been demonstrated that MPP⁺ administered intrastriatally to ratsproduces significant depletion of ATP as well as increased lactateconcentration confined to the striatum at the site of the injections.Compounds that enhance ATP production can protect against MPTP toxicityin mice.

A prodrug of Formula (I) is administered to animals such as mice or ratsfor three weeks before treatment with MPTP. MPTP is administered at anappropriate dose, dosing interval, and mode of administration for 1 weekbefore sacrifice. Control groups receive either normal saline or MPTPhydrochloride alone. Following sacrifice the two striate are rapidlydissected and placed in chilled 0.1 M perchloric acid. Tissue issubsequently sonicated and aliquots analyzed for protein content using afluorometer assay. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), andhomovanillic acid (HVA) are also quantified. Concentrations of dopamineand metabolites are expressed as nmol/mg protein.

Prodrugs of Formula (I) that protect against DOPAC depletion induced byMPTP, HVA, and/or dopamine depletion are neuroprotective and thereforecan be useful for the treatment of Parkinson's disease.

Haloperidol-Induced Hypolocomotion

The ability of a compound to reverse the behavioral depressant effectsof dopamine antagonists such as haloperidol, in rodents and isconsidered a valid method for screening drugs with potentialantiparkinsonian effects (Mandhane, et al., Eur. J. Pharmacol. 1997,328, 135-141). Hence, the ability of prodrugs of Formula (I) to blockhaloperidol-induced deficits in locomotor activity in mice can be usedto assess both in vivo and potential anti-Parkinsonian efficacy.

Mice used in the experiments are housed in a controlled environment andallowed to acclimatize before experimental use. One and one-half hoursbefore testing, mice are administered 0.2 mg/kg haloperidol, a dose thatreduces baseline locomotor activity by at least 50%. A test compound isadministered 5-60 min prior to testing. The animals are then placedindividually into clean, clear polycarbonate cages with a flatperforated lid. Horizontal locomotor activity is determined by placingthe cages within a frame containing a 3×6 array of photocells interfacedto a computer to tabulate beam interrupts. Mice are left undisturbed toexplore for 1 h, and the number of beam interruptions made during thisperiod serves as an indicator of locomotor activity, which is comparedwith data for control animals for statistically significant differences.

6-Hydroxydopamine Animal Model

The neurochemical deficits seen in Parkinson's disease can be reproducedby local injection of the dopaminergic neurotoxin, 6-hydroxydopamine(6-OHDA) into brain regions containing either the cell bodies or axonalfibers of the nigrostriatal neurons. By unilaterally lesioning thenigrostriatal pathway on only one-side of the brain, a behavioralasymmetry in movement inhibition is observed. Althoughunilaterally-lesioned animals are still mobile and capable of selfmaintenance, the remaining dopamine-sensitive neurons on the lesionedside become supersensitive to stimulation. This is demonstrated by theobservation that following systemic administration of dopamine agonists,such as apomorphine, animals show a pronounced rotation in a directioncontralateral to the side of lesioning. The ability of compounds toinduce contralateral rotations in 6-OHDA lesioned rats has been shown tobe a sensitive model to predict drug efficacy in the treatment ofParkinson's disease.

Male Sprague-Dawley rats are housed in a controlled environment andallowed to acclimatize before experimental use. Fifteen minutes prior tosurgery, animals are given an intraperitoneal injection of thenoradrenergic uptake inhibitor desipramine

(25 mg/kg) to prevent damage to nondopamine neurons. Animals are thenplaced in an anaesthetic chamber and anaesthetized using a mixture ofoxygen and isoflurane. Once unconscious, the animals are transferred toa stereotaxic frame, where anesthesia is maintained through a mask. Thetop of the head of an animal is shaved and sterilized using an iodinesolution. Once dry, a 2 cm long incision is made along the midline ofthe scalp and the skin retracted and clipped back to expose the skull. Asmall hole is then drilled through the skull above the injection site.In order to lesion the nigrostriatal pathway, the injection cannula isslowly lowered to position above the right medial forebrain bundle at−3.2 mm anterior posterior, −1.5 mm medial lateral from the bregma, andto a depth of 7.2 mm below the duramater. Two minutes after lowering thecannula, 6-OHDA is infused at a rate of 0.5 μL/min over 4 min, toprovide a final dose of 8 μg. The cannula is left in place for anadditional 5 min to facilitate diffusion before being slowly withdrawn.The skin is then sutured shut, the animal removed from the sterereotaxicframe, and returned to its housing. The rats are allowed to recover fromsurgery for two weeks before behavioral testing.

Rotational behavior is measured using a rotameter system havingstainless steel bowls (45 cm dia×15 cm high) enclosed in a transparentPlexiglas cover around the edge of the bowl and extending to a height of29 cm. To assess rotation, rats are placed in a cloth jacket attached toa spring tether connected to an optical rotameter positioned above thebowl, which assesses movement to the left or right either as partial(45°) or full (360°) rotations.

To reduce stress during administration of a test compound, rats areinitially habituated to the apparatus for 15 min on four consecutivedays. On the test day, rats are given a test compound, e.g., a prodrugof Formula (I). Immediately prior to testing, animals are given asubcutaneous injection of a subthreshold dose of apomorphine, and thenplaced in the harness and the number of rotations recorded for one hour.The total number of full contralatral rotations during the hour testperiod serves as an index of antiparkinsonian drug efficacy.

Example 60 Use of Clinical Trials to Assess the Efficacy of α-Amino AcidProdrugs for Treating Parkinson's Disease

The following clinical study may be used to assess the efficacy of acompound in treating Parkinson's disease.

Patients with idiopathic PD fulfilling the Queen Square Brain Bankcriteria (Gibb et al., J Neurol Neurosurg Psychiatry 1988, 51, 745-752)with motor fluctuations and a defined short duration GABA analogresponse (1.5-4 hours) are eligible for inclusion. Clinically relevantpeak dose dyskinesias following each morning dose of their currentmedication are a further pre-requisite. Patients are also required tohave been stable on a fixed dose of treatment for a period of at leastone month prior to starting the study. Patients are excluded if theircurrent drug regime includes slow-release formulations of L-Dopa, COMTinhibitors, selegiline, anticholinergic drugs, or other drugs that couldpotentially interfere with gastric absorption (e.g. antacids). Otherexclusion criteria include patients with psychotic symptoms or those onantipsychotic treatment, patients with clinically relevant cognitiveimpairment, defined as MMS (Mini Mental State) score of less than 24(Folstein et al., J Psychiatr Res 1975, 12, 189-198), risk of pregnancy,Hoehn & Yahr stage 5 in off-status, severe, unstable diabetes mellitus,and medical conditions such as unstable cardiovascular disease ormoderate to severe renal or hepatic impainnent. Full blood count, liver,and renal function blood tests are taken at baseline and aftercompletion of the study.

A randomized, double blind, and cross-over study design is used. Eachpatient is randomized to the order in which either LD/DC or one of thetwo dosages of test compound, e.g., an α-amino acid prodrug, isadministered in a single-dose challenge in double-dummy fashion in threeconsecutive sessions. Randomization is by computer generation of atreatment number, allocated to each patient according to the order ofentry into the study. All patients give informed consent.

Patients are admitted to a hospital for an overnight stay prior toadministration of test compound the next morning on three separateoccasions at weekly intervals. After withdrawal of all antiparkinsonianmedication from midnight the previous day, test compound is administeredat exactly the same time in the morning in each patient under fastingconditions.

Patients are randomized to the order of the days on which they receiveplacebo or test compound. The pharmacokinetics of a test compound can beassessed by monitoring plasma α-amino acid concentration over time.Prior to administration, a 22 G intravenous catheter is inserted in apatient's forearm. Blood samples of 5 ml each are taken at baseline and15, 30, 45, 60, 75, 90, 105, 120, 140, 160, 180, 210, and 240 minutesafter administering a test compound or until a full off state has beenreached if this occurs earlier than 240 minutes after drug ingestion.Samples are centrifuged immediately at the end of each assessment andstored deep frozen until assayed. Plasma α-amino acid levels aredetermined by high-pressure liquid chromatography (HPLC). On the lastassessment additional blood may be drawn for routine hematology, bloodsugar, liver, and renal function.

For clinical assessment, motor function is assessed using UPDRS (UnitedParkinson's Disease Rating Scale) motor score and BrainTest (Giovanni etal., J Neurol Neurosurg Psychiatry 1999, 67, 624-629), which is atapping test performed with the patient's more affected hand on thekeyboard of a laptop computer. These tests are carried out at baselineand then immediately following each blood sample until patients reachtheir full on-stage, and thereafter at 3 intervals of 20 min, and 30 minintervals until patients reach their baseline off-status. Once patientsreach their full on-state, video recordings are performed three times at20 min intervals. The following mental and motor tasks, which have beenshown to increase dyskinesia (Duriff et al., Mov Disord 1999, 14,242-245) are monitored during each video session: (1) sitting still for1 minute; (2) performing mental calculations; (3) putting on andbuttoning a coat; (4) picking up and drinking from a cup of water; and(5) walking. Videotapes are scored using, for example, versions of theGoetz Rating Scale and the Abnormal Involuntary Movements Scale todocument a possible increase in test compound induced dyskinesia. Actualoccurrence and severity of dyskinesia is measured with a DyskinesiaMonitor (Manson et al., J Neurol Neurosurg Psychiatry 2000, 68,196-201). The device is taped to a patient's shoulder on their moreaffected side. The monitor records during the entire time of achallenging session and provides a measure of the frequency and severityof occurring dyskinesias.

Results can be analyzed using appropriate statistical methods.

Example 61 Animal Model for Assessing Therapeutic Efficacy of α-AminoAcid Prodrugs for Treating Alzheimer's Disease

Heterozygous transgenic mice expressing the Swedish AD mutant gene,hAPPK670N, M671L (Tg2576; Hsiao, Learning & Memory 2001, 8, 301-308) areused as an animal model of Alzheimer's disease. Animals are housed understandard conditions with a 12:12 light/dark cycle and food and wateravailable ad libitum. Beginning at 9 months of age, mice are dividedinto two groups. The first two groups of animals receive increasingdoses of an α-amino acid prodrug, over six weeks. The remaining controlgroup receives daily saline injections for six weeks.

Behavioral testing is performed at each drug dose using the samesequence over two weeks in all experimental groups: 1) spatial reversallearning, 2) locomotion, 3) fear conditioning, and 4) shock sensitivity.This order is selected to minimize interference among testing paradigms.

Acquisition of the spatial learning paradigm and reversal learning aretested during the first five days of test compound administration usinga water T-maze as described in Bardgett et al., Brain Res Bull 2003, 60,131-142. Mice are habituated to the water T-maze during days 1-3, andtask acquisition begins on day 4. On day 4, mice are trained to find theescape platform in one choice arm of the maze until 6 to 8 correctchoices are made on consecutive trails. The reversal learning phase isthen conducted on day 5. During the reversal learning phase, mice aretrained to find the escape platform in the choice arm opposite from thelocation of the escape platform on day 4. The same performance criterionand inter-trial interval are used as during task acquisition.

Large ambulatory movements are assessed to determine that the results ofthe spatial reversal learning paradigm are not influenced by thecapacity for ambulation. After a rest period of two days, horizontalambulatory movements, excluding vertical and fine motor movements, areassessed in a chamber equipped with a grid of motion-sensitive detectorson day 8. The number of movements accompanied by simultaneous blockingand unblocking of a detector in the horizontal dimension are measuredduring a one-hour period.

The capacity of an animal for contextual and cued memory is tested usinga fear conditioning paradigm beginning on day 9. Testing takes place ina chamber that contains a piece of absorbent cotton soaked in anodor-emitting solution such as mint extract placed below the grid floor.A 5-min, 3 trial 80 db, 2800 Hz tone-foot shock sequence is administeredto train the animals on day 9. On day 10, memory for context is testedby returning each mouse to the chamber without exposure to the tone andfoot shock, and recording the presence or absence of freezing behaviorevery 10 seconds for 8 minutes. Freezing is defined as no movement, suchas ambulation, sniffing or stereotypy, other than respiration.

On day 11, the response of an animal to an alternate context and to theauditory cue is tested. Coconut extract is placed in a cup and the 80 dBtone is presented, but no foot shock is delivered. The presence orabsence of freezing in response to the alternate context is thendetermined during the first 2 minutes of the trial. The tone is thenpresented continuously for the remaining 8 minutes of the trial, and thepresence or absence of freezing in response to the tone is determined.

On day 12, the animals are tested to assess their sensitivity to theconditioning stimulus, i.e., foot shock.

Following the last day of behavioral testing, animals are anesthetizedand the brains removed, post-fixed overnight, and sections cut throughthe hippocampus. The sections are stained to image β-amyloid plaques(see e.g., Dong et al., Neuroscience 2004, 127, 601-609).

Data are analyzed using appropriate statistical methods.

Example 62 Animal Model for Assessing Therapeutic Efficacy of α-AminoAcid Prodrugs for Treating Huntington's Disease Neuroprotective Effectsin a Transgenic Mouse Model of Huntington's Disease

Transgenic HD mice of the N171-82Q strain and non-transgenic littermatesare treated with a prodrug of Formula (I) or a vehicle from 10 weeks ofage. The mice are placed on a rotating rod (“rotarod”). The length oftime at which a mouse falls from the rotarod is recorded as a measure ofmotor coordination. The total distance traveled by a mouse is alsorecorded as a measure of overall locomotion. Mice administered prodrugsof Formula (I) that are neuroprotective in the N171-82Q transgenic HDmouse model remain on the rotarod for a longer period of time and travelfurther than mice administered vehicle.

Malonate Model of Huntington's Disease

A series of reversible and irreversible inhibitors of enzymes involvedin energy generating pathways has been used to generate animal modelsfor neurodegenerative diseases such as Parkinson's and Huntington'sdiseases. In particular, inhibitors of succinate dehydrogenase, anenzyme that impacts cellular energy homeostasis, has been used togenerate a model for Huntington's disease (Brouillet et al., J.Neurochem. 1993, 60, 356-359; Beal et al., J. Neurosci. 1993, 13,4181-4192; Henshaw et al., Brain Research 1994, 647, 161-166; and Bealet al., J. Neurochem. 1993, 61, 1147-1150). The enzyme succinatedehydrogenase plays a central role in both the tricarboxylic acid cycleas well as the electron transport chain in mitochondria. Malonate is areversible inhibitor of succinate dehydrogenase. Intrastriatalinjections of malonate in rats have been shown to produce dose dependentstriatal excitotoxic lesions that are attenuated by both competitive andnoncompetitive NMDA antagonists (Henshaw et al., Brain Research 1994,647, 161-166). For example, the glutamate release inhibitor,lamotrigine, also attenuates the lesions. Co-injection with succinateblocks the lesions, consistent with an effect on succinatedehydrogenase. The lesions are accompanied by a significant reduction inATP levels as well as a significant increase in lactate levels in vivoas shown by chemical shift resonance imaging (Beal et al., J. Neurochem.1993, 61, 1147-1150). The lesions produce the same pattern of cellularsparing, which is seen in Huntington's disease, supporting malonatechallenge as a useful model for the neuropathologic and neurochemicalfeatures of Huntington's disease.

To evaluate the effect of α-amino acid prodrugs of Formula (I) in thismalonate model for Huntington's disease, a prodrug of Formula (I) isadministered at an appropriate dose, dosing interval, and route, to maleSprague-Dawley rats. A prodrug is administered for two weeks prior tothe administration of malonate and then for an additional week prior tosacrifice. Malonate is dissolved in distilled deionized water and the pHadjusted to 7.4 with 0.1 M HCl. Intrastriatal injections of 1.5 μL of 3μmol malonate g are made into the left striatum at the level of theBregma 2.4 mm lateral to the midline and 4.5 mm ventral to the dura.Animals are sacrificed at 7 days by decapitation and the brains quicklyremoved and placed in ice cold 0.9% saline solution. Brains aresectioned at 2 mm intervals in a brain mold. Slices are then placedposterior side down in 2% 2,3,5-tiphenyltetrazolium chloride. Slices arestained in the dark at room temperature for 30 min and then removed andplaced in 4% paraformaldehyde pH 7.3. Lesions, noted by pale staining,are evaluated on the posterior surface of each section. The measurementsare validated by comparison with measurements obtained on adjacent Nisslstain sections. Compounds exhibiting a neuroprotective effect andtherefore potentially useful in treating Huntington's disease show areduction in malonate-induced lesions.

Example 63 Animal Models of Pain Inflammatory Pain—Formalin Test

A formalin assessment test is performed according to the proceduredescribed by Dubuisson and Dennis, Pain 1977, 4, 161-174. Fifty μL of a5% formalin solution is injected subcutaneously into the dorsal aspectof the right hind paw and the rats are then individually placed intoclear observation cages. Rats are observed for a continuous period of 60min or for periods of time corresponding to phase I (from 0 to 10 minfollowing formalin injection) and phase 11 (from 30 to 50 min followingformalin injection) of the formalin test (Abbott et al., Pain 1995, 60,91-102). The number of flinching behaviors of the injected paw isrecorded using a sampling technique in which each animal is observed forone 60-sec period during each 5-min interval. Test compound isadministered 30 min or other appropriate interval prior to formalininjection.

Inflammatory Pain—Carrageenan-Induced Acute Thermal Hyperalgesia andEdema

Paw edema and acute thermal hyperalgesia are induced by injecting 100 μLof a 1% solution of α-carrageenan in physiological saline into theplantar surface of the right hind paw. Thermal hyperalgesia isdetermined 2 h following carrageenan injection, using a thermal pawstimulator as described by Hargreaves et al., Pain 1988, 32, 77-88. Ratsare placed into plastic cubicles mounted on a glass surface maintainedat 30° C. and a thermal stimulus in the form of radiant heat emittedfrom a focused projection bulb is then applied to the plantar surface ofeach hind paw. The stimulus current is maintained at 4.50±0.05 Amp, andthe maximum time of exposure is set at 20.48 sec to limit possibletissue damage. The elapsed time until a brisk withdrawal of the hind pawfrom the thermal stimulus is recorded automatically using photodiodemotion sensors. The right and left hind paw of each rat is tested inthree sequential trials at about 5-min intervals. Carrageenan-inducedthermal hyperalgesia of paw withdrawal latency (PWL_(thermal)) iscalculated as the mean of the two shortest latencies. Test compound isadministered 30 min before assessment of thermal hyperalgesia.

The volume of paw edema is measured using water displacement with aplethysmometer 2 h following carrageenan injection by submerging the pawup to the ankle hairline (approx. 1.5 cm). The displacement of thevolume is measured by a transducer and recorded. Test compound isadministered at an appropriate time following carrageenan injection,such as for example, 30 min or 90 min.

Visceral Pain

Thirty min following administration of test compound, mice receive aninjection of 0.6% acetic acid in sterile water (10 mL/kg, i.p.) asdescribed by Mogil et al., Pain 1999, 80, 67-82. Mice are then placed intable-top Plexiglass observation cylinders (60 cm high×40 cm diameter)and the number of constrictions/writhes (a wave of mild constriction andelongation passing caudally along the abdominal wall, accompanied by aslight twisting of the trunk and followed by bilateral extension of thehind limbs) is recorded during the 5-20 min following acetic acidinjection for a continuous observation period of 15 min.

Neuropathic Pain—Spinal Nerve Ligation

Rats receive unilateral ligation of the lumbar 5 (L5) and lumbar 6 (L6)spinal nerves as described by Kim and Chung, Pain 1992, 50, 355-363. Theleft L5 and L6 spinal nerves of the rat are isolated adjacent to thevertebral column and tightly ligated with a 5-0 silk suture distal tothe dorsal root ganglia, and care is taken to avoid injury of the lumbar4 (L4) spinal nerve. Control rats undergo the same procedure but withoutnerve ligation. All animals are allowed to recover for at least 1 weekand not more than 3 weeks prior to assessment of mechanical allodynia.Mechanical allodynia is measure using calibrated von Frey filaments asdescribed by Chaplan et al., J Neurosci Methods 1994, 53, 55-63. Ratsare placed into inverted plastic containers (20×12.5×20 cm) on top of asuspended wire mesh grid and acclimated to the test chamber for 20 min.The von Frey filaments are presented perpendicularly to the plantarsurface of the selected hind paw, and then held in this position forapproximately 8 s with enough force to cause a slight bend in thefilament. Positive responses include an abrupt withdrawal of the hindpaw from the stimulus or flinching behavior immediately followingremoval of the stimulus. A 50% paw withdrawal threshold (PWT) isdetermined using the procedure described by Dixon, Rev Pharmacol Toxicol1980, 20, 441-462. Rats with a PWT≦5.0 g are considered allodynic andutilized to test the analgesic activity of a test compound. The testcompound can be administered 30 min prior to the assessment ofmechanical allodynia.

Neuropathic Pain—Chronic Constriction Injury of the Sciatic Nerve

A model of chronic constriction injury of the sciatic nerve-inducedneuropathic pain according to the method of Bennett and Xie, Pain 1988,33, 87-107, is used. The right common sciatic nerve is isolated atmid-thigh level and loosely ligated by four chromic gut (4-0) tiesseparated by an interval of 1 mm. Control rats undergo the sameprocedure but without sciatic nerve constriction. All animals areallowed to recover for at least 2 weeks and for no more than 5 weeksprior to testing of mechanical allodynia. Allodynic PWT is assessed inthe animals as described for animals with spinal nerve ligation. Onlyrats with a PWT≦5.0 g are considered allodynic and utilized to evaluatethe analgesic activity of a test compound. Test compound is administered30 min or other appropriate time prior to the assessment of mechanicalallodynia.

Neuropathic Pain—Vincristine-Induced Mechanical Allodynia

A model of chemotherapy-induced neuropathic pain is produced bycontinuous intravenous vincristine infusion (Nozaki-Taguchi et al., Pain20.01, 93, 69-76). Anesthetized rats undergo a surgical procedure inwhich the jugular vein is catheterized and a vincristine-primed pump isimplanted subcutaneously. Fourteen days of intravenous infusion ofvincristine (30 μg/kg/day) results in systemic neuropathic pain of theanimal. Control animals undergo the same surgical procedure, withphysiological saline infusion. PWT of the left paw is assessed in theanimals 14 days post-implantation as described for the spinal nerveligation model. Test compound is administered 30 min prior to the testfor mechanical allodynia in rats with PWT≦5.00 g before treatment.

Post-Operative Pain

A model of post-operative pain is performed in rats as described byBrennan et al., Pain 1996, 64, 493-501. The plantar aspect of the lefthind paw is exposed through a hole in a sterile plastic drape, and a1-cm longitudinal incision is made through the skin and fascia, starting0.5 cm from the proximal edge of the heel and extending towards thetoes. The plantaris muscle is elevated and incised longitudinallyleaving the muscle origin and insertion points intact. After hemostasisby application of gently pressure, the skin is opposed with two mattresssutures using 5-0 nylon. Animals are then allowed to recover for 2 hfollowing surgery, at which time mechanical allodynia and thermalhyperalgesia are assessed.

Effects of test compound on mechanical allodynia are assessed 30 minfollowing administration, with PWT being examined in these animals forboth the injured and non-injured paw as described for the spinal nerveligation model with the von Frey filament systematically pointingtowards the medial side of the incision. In a separate experiment, theeffects of test compound on thermal hyperalgesia are assessed 30 minfollowing administration of test compound, with PWL_(thermal) beingdetermined as described for the carrageen-induced thermal hyperalgesiamodel with the thermal stimulus applied to the center of the incision ofthe paw planter aspect.

Example 64 Animal Models to Assess the Efficacy of α-Amino Acid Prodrugsfor Treating Social Phobia Fear-Potentiated Startle Model

The fear-potentiated startle paradigm, e.g., increased startle in thepresence of a conditioned fear stimulus (CFS), is a learned fearparadigm that has been shown to involve the central amygdala (see, e.g.,Davis, Behav. Neurosci. 1986, 100, 814-824; and Helton et al., J.Pharmacol. Exp. Ther 1998, 284, 651-660). Fear potentiated startleevokes a neurological process that mimics the behavioral pathologymanifest in post-traumatic stress disorder and other anxiety-baseddiseases. Elevated anxiety impairs sensory processing with consequentdeterioration of memory, cognition, and social function. Anxiogenicstates seen in human conditions such as generalized social phobia (Steinet al., Arch. Gen. Psychiatry 2002, 59, 1027-1034) or drug-inducedanimal models of anxiety (Sanders and Shekhar, Pharmacol. Biochem.Behav. 1995, 52, 701-706) are accompanied by abnormal amygdala function.Human studies have demonstrated that both the baseline andfear-potentiated responses can be inhibited by anxiolytic drugs such asthe benzodiazepine, alprazolam (Riba et al., Psychopharmacology (Berl)2001, 157, 358-367). Measures of fear-potentiated startle response inrats and humans provide a good indication for the potential anxiolyticactivity of a drug (see e.g., Belzung, Current Opinion inInvestigational Drugs. 2001, 2(8), 1108-1111; and Nestler et al.,Neuron, 2002, 34, 13-25). Thus, these known models can be used toconfirm the efficacy of one or more compounds of Formula (I) astherapies for affective disorders.

Male Sprague-Dawley rats weighing 350-450 g are used. Animals aremaintained on a 12:12 hour light-dark cycle with food and watercontinuously available. Animals are trained and tested in 8×15×15 cm³Plexiglas™ and wire-mesh cages. Each cage floor consists of four 6 mmdiameter stainless-steel bars spaced 18 mm apart. Each cage is suspendedbetween compression springs within a steel frame and located within a90×70×70 cm³ ventilated sound-attenuating chamber. Background noise (60dB wide-band) is provided by a noise generator and delivered throughhigh-frequency speakers located 5 cm in front of each cage. Sound levelmeasurements (sound pressure level) are made with a sound-level meter (Ascale; random input) with a microphone located 7 cm from the center ofthe speaker (approximating the distance of the rat's ear from thespeaker).

Startle responses are evoked by 50 msec, 95 dB white noise bursts (5msec rise-decay) delivered through the same speakers used to providebackground noise. An accelerometer affixed to the bottom of each cageproduces a voltage output proportional to the velocity of cage movement.This output is amplified and digitized. Startle amplitude is defined asthe maximal peak-to-peak voltage that occurs during the first 200 msecafter onset of the startle-eliciting stimulus.

The conditioned stimulus (CS) is a 3.7 sec light (80 lux) produced by an8 W fluorescent bulb (100 msec rise time) located 10 cm behind eachcage. Luminosity is measured using a light meter. The US is a 0.5 secondshock, delivered to the floorbars and produced by a shock generator.Shock intensities (measured as in, for example, Cassella et al., PhysiolBehav 1986, 36, 1187-91) are 0.4 mA.

Test compounds are administered prior to evaluation. To match theanimals for assessment, on each of the next 2 days animals are placed inthe test chambers and presented with 30 95 dB noise bursts at a 30 secinterstimulus interval (ISI). The mean startle amplitude across the 30stimuli on the second day is used to divide rats into groups withsimilar startle amplitudes.

To fear condition the test animals, on each of the next 2 days, rats arereturned to the test chambers and 5 min later given the first of 10light-footshock pairings. The 0.4 mA 0.5 sec shock is delivered duringthe last 0.5 sec of the 3.7 sec light. The average intertrial interval(ITI) is 4 min (range, 3-5 min).

Twenty-four (24) hours after the last fear conditioning session, testcompound or vehicle is administered to the rats and the rats areimmediately placed into the test chambers. After 5 min the rats receive30 95 dB noise bursts (30 sec ISI) to habituate the startle response toa stable baseline prior to the test trials. Each test trial (18 total)involves the presentation of a noise burst of one of 3 intensities (95,100, or 105 dB); half of these occurring in the presence and half in theabsence of the light CS. On the CS trials the startle stimulus ispresented 3.2 sec after the onset of the 3.7 sec light. Trial types arepresented in a balanced, irregular order (30 sec ITI) with therestriction that each of the 6 trial types occur once within each of the3 trial blocks.

The initial startle stimuli of the test session are used to habituatestartle responses to asymptotic levels and are not included instatistical analyses. Subsequent startle responses generated by thethree different startle intensities are averaged for each animal toobtain a single score for both the startle stimulus alone (baseline) andthe CS and startle stimulus trials. A difference score is computed foreach animal by subtracting the mean baseline startle amplitudes from themean startle amplitudes in the presence of the CS. Analysis of the datais performed using appropriate statistical methods.

Activity and Functional Observation Measurements

Rats are dosed with vehicle or test compound from postnatal day 25 topost natal day 70. The locomotor activity of 10 randomly selectedrats/sex/group is measured on postnatal day 30 (adolescent) andpostnatal day 72 (adult). On postnatal day 30 and postnatal day 72, eachrat is placed in a shoebox cage equipped with the automated PhotobeamActivity System. Locomotor activity is monitored during a 60 min sessioncomposed of 12, 5-min intervals. The total number of photobeam breaksthat occur during each of the 12, 5-min intervals is recorded. Changesin habituation to novel environments are assessed by comparing locomotoractivity over 3 session intervals between the control versus test groupsfor habituation. Emotionality is determined by following behavioralfacets including defecation, urination, rearing, grooming, and backing(see e.g., Hall, J. Comp. Physiol. Psychol., 1936, 22, 325-352; andSpyker, in Behavioral Toxicology, Ed. Weiss and Laties, Plenum Press,New York, pp 311-349, 1975). A functional observation battery isperformed on postnatal day 75 according to the parameters described byIrwin, Psychopharmacologia 1968, 13, 222-257, to evaluate gait, posture,abnormal behavior, and vocalization.

Spatial Navigation in an M Swim Maze

Drugs with anxiolytic or anti-depression activity often demonstrateunwanted side-effects, such as sedation, amnesia or other cognitiveimpairment, hyperactivity, or hypoactivity. A standard test for theseunwanted side-effects is to quantify activity and emotionality to anovel surrounding in rats after repeated exposure to drug. An additionaltest to measure effects of a drug on aspects of learning and memory isthe M Swim Maze.

The M Swim Maze was developed to test spatial learning and memory (e.g.,functional memory). The animal has no visual or spatial cues in the pooland must rely on extra-maze cues (e.g., light setup outside the poolthat can be seen by the swimming animal). Through a series of trials arat develops “place learning” or knowledge about the position of theescape platform based upon the extra-maze cues. The platform can bemoved to a different arm of the M configuration each day, combiningspatial memory with working memory. This paradigm involves extinction ofthe prior memory and resolution of a new spatial problem. Many drugsthat have anxiolytic or anti-depressive effects have detrimental effectson functional memory important for daily life. Additionally, spatiallearning and memory tasks in rodents during stressful activities, suchas escape from water, are useful to evaluate drugs for unwanted sideeffects of impairment of functional memory. Results in rodents correlatewell to those in humans and other mammals. Decreased performance in thismodel indicates a negative locomotor or cognitive side-effect of drugtreatment. An improvement may indicate improved cognition due to reducedstress or anxiety from task performance.

As an example, vehicle or test compound is administered to rats onpostnatal day 25 through postnatal day 70 (45 days). Learning and memoryare evaluated in a water M-maze. The evaluation consists of 10trials/day for each animal on 4 successive days to assess short-termmemory. The animals are evaluated for their ability to escape from themaze via a platform located on the lighted arm of an M-shaped maze.After placement of the animal in the central arm of the M-shaped maze,the goal side is varied for each animal at each trial according to apredetermined computer generated sequence. The same animals are alsotested 5 days after the initial testing to assess long-term memory. Onthat day each animal is allowed 10 trials in the maze and time to escapeis measured. Analysis of the data is performed using appropriatestatistical analysis methods.

Social Interaction Test

The Social Interaction Test is another test that can be used to assessanxiolytic properties (see e.g., File and Hyde, Pharmacol Biochem Behav1979, Jul. 11(1), 65-69).

Rats are allowed to acclimate to the animal care facility for 5 days andare housed singly for 5 days prior to testing with free access to foodand water. Animals are handled for 5 min per day. The design andprocedure for the Social Interaction Test can be performed as describedby Kennett et al., Neuropharmacology 1997, 36(4-5), 601-608). On thetest day, weight matched pairs of rats, unfamiliar to each other, aregiven identical treatments and returned to their home cages. Animals arerandomly divided into treatment groups and are administered testcompound, vehicle, or chlordiazepoxide (5 mg/kg). Dosing is at least 1hr prior to testing. Rats are subsequently placed in a white Perspextest box or arena (54×37×26 cm³) in which the floor is divided up into24 equal squares, for 15 min. Background noise is applied. Sessions arevideotaped. Active social interaction, defined as time involved ingrooming, sniffing, biting, boxing, wrestling, following, and crawlingover or under, is scored. The number of episodes of rearing (animalcompletely rises up its body on its hind limbs), grooming (licking,biting, scratching of body), and face washing (i.e., hands are movedrepeatedly over face), and number of squares crossed are scored. Passivesocial interaction (animals lying beside or on top of each other) is notscored. The social interaction data is analyzed by appropriatestatistical methods.

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein, butmay be modified within the scope and equivalents thereof.

1-36. (canceled)
 37. A compound of Formula (I):

a pharmaceutically acceptable salt of any of the foregoing, or apharmaceutically acceptable solvate of any of the foregoing, wherein: R¹is chosen from alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl; R² and R³ are independently chosen fromhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substitutedcycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; or R² and R³ together with the carbon atom to whichthey are bonded form a ring chosen from a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, and substituted cycloheteroalkyl ring; R⁴is chosen from hydrogen and methyl; R⁵ and R⁶ together with the carbonatom to which they are bonded form a ring chosen from a 1,1-cyclopropanering and a substituted 1,1-cyclopropane ring.
 38. The compound of claim37, wherein R¹ is chosen from C₂₋₄ alkyl, phenyl, substituted phenyl,cyclohexyl, and substituted cyclohexyl; R² is chosen from hydrogen andC₁₋₄ alkyl; and R³ is hydrogen.
 39. The compound of claim 37, wherein R⁴is hydrogen.
 40. The compound of claim 39, wherein R¹ is chosen fromC₁₋₆ alkyl, phenyl, substituted phenyl, cyclohexyl, substitutedcyclohexyl, C₇₋₉ phenylalkyl, and adamantyl; R² is chosen from hydrogenand C₁₋₄ alkyl; and R³ is hydrogen.
 41. The compound of claim 37,wherein R¹ is chosen from C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₀aryl, substituted C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, substituted C₃₋₇cycloalkyl, C₆₋₁₀ arylalkyl, and C₆₋₁₀ substituted arylalkyl.
 42. Thecompound of claim 37, wherein R¹ is chosen from C₁₋₄ alkyl, phenyl,substituted phenyl, cyclohexyl, substituted cyclohexyl, styryl, andsubstituted styryl.
 43. The compound of claim 37, wherein R¹ is chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl.
 44. The compound ofclaim 37, wherein each substituent group is independently chosen fromhalogen, C₁₋₃ alkyl, —OH, —NH₂, —SH, C₁₋₃ alkoxy, C₁₋₃ acyl, C₁₋₃thioalkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylamino, and C₁₋₃ dialkylamino.45. The compound of claim 37, wherein R² and R³ are independently chosenfrom hydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₀ aryl,substituted C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, and substituted C₃₋₇cycloalkyl.
 46. The compound of claim 37, wherein R² and R³ areindependently chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl,phenyl, and cyclohexyl.
 47. The compound of claim 37, wherein R² ishydrogen; and R³ is chosen from hydrogen, methyl, ethyl, n-propyl,isopropyl, phenyl, and cyclohexyl.
 48. The compound of claim 37, whereinR¹ is chosen from C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₀ aryl,substituted C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, substituted C₃₋₇ cycloalkyl,C₆₋₁₀ arylalkyl, and C₆₋₁₀ substituted arylalkyl; and R² and R³ areindependently chosen from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, and substitutedC₃₋₇ cycloalkyl.
 49. The compound of claim 37, wherein R¹ is chosen frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl; R² is hydrogen; andR³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl,and cyclohexyl.
 50. A pharmaceutical composition comprising at least onepharmaceutically acceptable vehicle and at least one compound of claim37.
 51. The pharmaceutical composition of claim 50, wherein thepharmaceutical composition is formulated for oral administration. 52.The pharmaceutical composition of claim 51, wherein the pharmaceuticalcomposition is a sustained release oral formulation.
 53. Thepharmaceutical composition of claim 50, wherein the at least onecompound of Formula (I) is present in an amount effective for thetreatment of a disease in a patient, wherein the disease is chosen frompost-partum depression, premenstrual syndrome, premenstrual dysphoricdisorder, a learning disorder, autistic disorder, attention-deficithyperactivity disorder, Tourette's syndrome, phobia, post-traumaticstress disorder, dementia, AIDS dementia, Alzheimer's disease,Parkinson's disease, Huntington's disease, spasticity, myoclonus, musclespasm, depression, anxiety, bipolar disorder, a substance abusedisorder, and urinary incontinence.
 54. The pharmaceutical compositionof claim 50, wherein the disease is schizophrenia.
 55. A method oftreating a disease in a patient, wherein the disease is chosen frompost-partum depression, premenstrual syndrome, premenstrual dysphoricdisorder, a learning disorder, autistic disorder, attention-deficithyperactivity disorder, Tourette's syndrome, phobia, post-traumaticstress disorder, dementia, AIDS dementia, Alzheimer's disease,Parkinson's disease, Huntington's disease, spasticity, myoclonus, musclespasm, depression, anxiety, bipolar disorder, a substance abusedisorder, and urinary incontinence, comprising administering to apatient in need of such treatment a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof claim 37 and at least on pharmaceutically acceptable vehicle.
 56. Themethod of claim 55, wherein the disease is schizophrenia.
 57. The methodof claim 55, wherein the pharmaceutical composition is a sustainedrelease oral dosage form.
 58. The method of claim 55, wherein thepharmaceutical composition is administered to the patient once or twiceper day.
 59. The method of claim 55, comprising administering atherapeutically effective amount of at least one additional therapeuticagent.
 60. The method of claim 59, wherein the at least one additionaltherapeutic agent is chosen from an antipsychotic, an antidepressant, ananxiolytic, an anti-anxiety agent, a sedative, and a hypnotic.